Acyloxyalkyl carbamate prodrugs, methods of synthesis and use

ABSTRACT

The disclosures herein relate generally to acyloxyalkyl carbamate prodrugs of (±)-4-amino-3-(4-chlorophenyl)butanoic acid and analogs thereof, pharmaceutical compositions thereof, methods of making prodrugs of (±)-4-amino-3-(4-chlorophenyl)butanoic acid and analogs thereof, methods of using prodrugs of (±)-4-amino-3-(4-chlorophenyl)butanoic acid and analogs thereof, and pharmaceutical compositions thereof for treating or preventing common diseases and/or disorders such as spasticity and/or acid reflux disease. The disclosures herein also relate to acyloxyalkyl carbamate prodrugs of (±)-4-amino-3-(4-chlorophenyl)butanoic acid and analogs thereof which are suitable for oral administration and to sustained release oral dosage forms thereof.

This application claims the benefit under 35 U.S.C. §119(e) from U.S.Provisional Application Ser. No. 60/496,938, filed Aug. 20, 2003 andU.S. Provisional Application Ser. No. 60/606,637, filed Aug. 13, 2004entitled “Methods for Synthesis of Acyloxyalkyl Carbamate Prodrugs”which are herein incorporated by reference in their entirety.

1. TECHNICAL FIELD

The disclosures herein relate generally to acyloxyalkyl carbamateprodrugs of (±)-4-amino-3-(4-chlorophenyl)butanoic acid and analogsthereof, pharmaceutical compositions thereof, methods of making prodrugsof (±)-4-amino-3-(4-chlorophenyl)butanoic acid and analogs thereof andmethods of using prodrugs of (±)-4-amino-3-(4-chlorophenyl)butanoic acidand analogs thereof and pharmaceutical compositions thereof to treatvarious diseases or disorders. The disclosures herein also relate tosuch prodrugs suitable for oral administration and for oraladministration using sustained release dosage forms.

2. BACKGROUND

(±)-4-Amino-3-(4-chlorophenyl)butanoic acid (baclofen), (1), is ananalog of gamma-aminobutyric acid (i.e., GABA) that selectivelyactivates GABA_(B) receptors, resulting in neuronal hyperpolarization.GABA_(B) receptors are located in laminae I-IV of the spinal cord, whereprimary sensory fibers end. These G-protein coupled receptors activateconductance by K⁺-selective ion channels and can reduce currentsmediated by Ca²⁺ channels in certain neurons. Baclofen has a presynapticinhibitory effect on the release of excitatory neurotransmitters andalso acts postsynaptically to decrease motor neuron firing (see Bowery,Trends Pharmacol. Sci. 1989, 10, 401-407; Misgeld et al., Prog.Neurobiol. 1995, 46, 423-462).

Many examples of compounds having agonistic or partially agonisticaffinity to GABA_(B) receptors exist and include certain amino acids,aminophosphonic acids, aminophosphinic acids, aminophosphonous acids andaminosulfinic acids such as, for example,

-   4-amino-3-(2-chlorophenyl)butanoic acid;-   4-amino-3-(4-fluorophenyl)butanoic acid;-   4-amino-3-hydroxybutanoic acid;-   4-amino-3-(4-chlorophenyl)-3-hydroxyphenylbutanoic acid;-   4-amino-3-(thien-2-yl)butanoic acid;-   4-amino-3-(5-chlorothien-2-yl)butanoic acid;-   4-amino-3-(5-bromothien-2-yl)butanoic acid;-   4-amino-3-(5-methylthien-2-yl)butanoic acid;-   4-amino-3-(2-imidazolyl)butanoic acid;-   4-guanidino-3-(4-chlorophenyl)butanoic acid;-   (3-aminopropyl)phosphonous acid;-   (4-aminobut-2-yl)phosphonous acid;-   (3-amino-2-methylpropyl)phosphonous acid;-   (3-aminobutyl)phosphonous acid;-   (3-amino-2-(4-chlorophenyl)propyl)phosphonous acid;-   (3-amino-2-(4-chlorophenyl)-2-hydroxypropyl)phosphonous acid;-   (3-amino-2-(4-fluorophenyl)propyl)phosphonous acid;-   (3-amino-2-phenylpropyl)phosphonous acid;-   (3-amino-2-hydroxypropyl)phosphonous acid;-   (E)-(3-aminopropen-1-yl)phosphonous acid;-   (3-amino-2-cyclohexylpropyl)phosphonous acid;-   (3-amino-2-benzylpropyl)phosphonous acid;-   [3-amino-2-(4-methylphenyl)propyl]phosphonous acid;-   [3-amino-2-(4-trifluoromethylphenyl)propyl]phosphonous acid;-   [3-amino-2-(4-methoxyphenyl)propyl]phosphonous acid;-   [3-amino-2-(4-chlorophenyl)-2-hydroxypropyl]phosphonous acid;-   (3-aminopropyl)methylphosphinic acid;-   (3-amino-2-hydroxypropyl)methylphosphinic acid;-   (3-aminopropyl)(difluoromethyl)phosphinic acid;-   (4-aminobut-2-yl)methylphosphinic acid;-   (3-amino-1-hydroxypropyl)methylphosphinic acid;-   (3-amino-2-hydroxypropyl)(difluoromethyl)phosphinic acid;-   (E)-(3-aminopropen-1-yl)methylphosphinic acid;-   (3-amino-2-oxo-propyl)methyl phosphinic acid;-   (3-aminopropyl)hydroxymethylphosphinic acid;-   (5-aminopent-3-yl)methylphosphinic acid;-   (4-amino-1,1,1-trifluorobut-2-yl)methylphosphinic acid;-   3-aminopropylsulfinic acid;-   (3-amino-2-(4-chlorophenyl)propyl)sulfinic acid;-   (3-amino-2-hydroxypropyl)sulfinic acid;-   (2S)-(3-amino-2-hydroxypropyl)sulfinic acid;-   (2R)-(3-amino-2-hydroxypropyl)sulfinic acid;-   (3-amino-2-fluoropropyl)sulfinic acid;-   (2S)-(3-amino-2-fluoropropyl)sulfinic acid;-   (2R)-(3-amino-2-fluoropropyl)sulfinic acid; and-   (3-amino-2-oxopropyl)sulfinic acid.

A principal pharmacological effect of baclofen in mammals is reductionof muscle tone and the drug is frequently used in the treatment ofspasticity. Spasticity is associated with damage to the corticospinaltract and is a common complication of neurological disease. Diseases andconditions in which spasticity may be a prominent symptom includecerebral palsy, multiple sclerosis, stroke, head and spinal cordinjuries, traumatic brain injury, anoxia and neurodegenerative diseases.Patients with spasticity complain of stiffness, involuntary spasm andpain. These painful spasms may be spontaneous or triggered by a minorsensory stimulus, such as touching the patient.

Baclofen is useful in controlling gastro-esophageal reflux disease (vanHerwaarden et al., Aliment. Pharmacol. Ther. 2002, 16, 1655-1662;Ciccaglione et al., Gut 2003, 52, 464-470; Andrews et al., U.S. Pat. No.6,117,908; Fara et al., International Publication No. WO02/096404); inpromoting alcohol abstinence in alcoholics (Gessa et al., InternationalPublication No. WO01/26638); in promoting smoking cessation (Gessa etal., International Publication No. WO01/08675); in reducing addictionliability of narcotic agents (Robson et al., U.S. Pat. No. 4,126,684);in the treatment of emesis (Bountra et al., U.S. Pat. No. 5,719,185) andas an anti-tussive for the treatment of cough (Kreutner et al., U.S.Pat. No. 5,006,560).

Baclofen may be administered orally or by intrathecal delivery through asurgically implanted programmable pump. The drug is rapidly absorbedfrom the gastrointestinal tract and has an elimination half-life ofapproximately 3-4 hours. Baclofen is partially metabolized in the liverbut is largely excreted by the kidneys unchanged. The short half-life ofbaclofen necessitates frequent administration with typical oral dosingregimens ranging from about 10 to about 80 mg of three or four divideddoses daily. Plasma baclofen concentrations of about 80 to about 400ng/mL result from these therapeutically effective doses in patients(Katz, Am. J. Phys. Med. Rehabil. 1988, 2, 108-116; Krach, J. ChildNeurol. 2001, 16, 31-36). When baclofen is given orally, sedation is aside effect, particularly at elevated doses. Impairment of cognitivefunction, confusion, memory loss, dizziness, weakness, ataxia andorthostatic hypotension are other commonly encountered baclofenside-effects.

Intrathecal administration is often recommended for patients who findthe adverse effects of oral baclofen intolerable. The intrathecal use ofbaclofen permits effective treatment of spasticity with doses less than1/100^(th) of those required orally, since administration directly intothe spinal subarachnoid space permits immediate access to the GABA_(B)receptor sites in the dorsal horn of the spinal cord. Surgicalimplantation of a pump is, however, inconvenient and a variety ofmechanical and medical complications can arise (e.g., catheterdisplacement, kinking or blockage, pump failure, sepsis and deep veinthrombosis). Acute discontinuation of baclofen therapy (e.g., in casesof mechanical failure) may cause serious withdrawal symptoms such ashallucinations, confusion, agitation and seizures (Sampathkumar et al.,Anesth. Analg. 1998, 87, 562-563).

While the clinically prescribed baclofen product (Lioresal™) isavailable only as a racemate, the GABA_(B) receptor agonist activityresides entirely in one enantiomer, R-(−)-baclofen (2) (also termedL-baclofen).

The other isomer, S-baclofen, actually antagonizes the action ofR-baclofen at GABA_(B) receptors and its antinociceptive activity in therat spinal cord (Terrence et al., Pharmacology 1983, 27, 85-94; Sawynoket al. Pharmacology 1985, 31, 248-259). Orally administered R-baclofenis reported to be about 5-fold more potent than orally administeredracemic baclofen, with an R-baclofen regimen of 2 mg t.i.d beingequivalent to racemic baclofen at 10 mg t.i.d. (Fromm et al., Neurology1987, 37, 1725-1728). Moreover, the side effect profile, followingadministration of R-baclofen, has been shown to be significantlyreduced, relative to equally efficacious dose of racemic baclofen.

Baclofen, a zwitterionic amino acid, lacks the requisite physicochemicalcharacteristics for effective passive permeability across cellularmembranes. Passage of the drug across the gastrointestinal tract and theblood-brain barrier (BBB) are mediated primarily by active transportprocesses, rather than by passive diffusion. Accordingly, baclofen is asubstrate for active transport mechanisms shared by neutral α-aminoacids like leucine, and β-amino acids like β-alanine and taurine (vanBree et al., Pharm. Res. 1988, 5, 369-371; Cercos-Fortea et al.,Biopharm. Drug. Disp. 1995, 16, 563-577; Deguchi et al., Pharm. Res.1995, 12, 1838-1844; Moll-Navarro et al., J. Pharm. Sci. 1996, 85,1248-1254). Transport across the BBB is stereoselective, withpreferential uptake of the active R-enantiomer (2) being reported (vanBrec et al., Pharm. Res. 1991, 8, 259-262). In addition, organic aniontransporters localized in capillary endothelial cells of the blood-brainbarrier have been implicated in efflux of baclofen from the brain(Deguchi et al., supra; Ohtsuki et al., J. Neurochem. 2002, 83, 57-66).3-(p-Chlorophenyl)pyrrolidine has been described as a CNS-penetrableprodrug of baclofen (Wall et al., J. Med. Chem. 1989, 32, 1340-1348).Prodrugs of other GABA analogs are described in Bryans et al.,International Publication No. WO01/90052; Bryans et al., EPI 178034;Cundy et al., U.S. Patent Application Publication No. 2002/0151529;Gallop et al., U.S. Patent Application Publication No. 2003/0176398;Gallop et al., U.S. Patent Application Publication No. 2003/0171303;Gallop et al., U.S. Patent Application Publication No. 2004/0006132; andRaillard et al., U.S. Patent Application Publication No. 2004/0014940.

Sustained released oral dosage formulations are a conventional solutionto the problem of rapid systemic drug clearance, as is well known in theart (see, e.g., “Remington's Pharmaceutical Sciences,” PhiladelphiaCollege of Pharmacy and Science, 19th Edition, 1995). Osmotic deliverysystems are also recognized methods for sustained drug delivery (See,e.g., Verma et al., Drug Dev. Ind. Pharm. 2000, 26, 695-708). Successfulapplication of these technologies depends on the drug of interest havingan effective level of absorption from the large intestine (also referredto herein as the colon), where the dosage form spends a majority of itstime during its passage down the gastrointestinal tract. Baclofen ispoorly absorbed following administration into the colon in animal models(Merino et al., Biopharm. Drug. Disp. 1989, 10, 279-297), presumably,since the transporter proteins mediating baclofen absorption in theupper region of the small intestine are not expressed in the largeintestine. Development of an oral controlled release formulation forbaclofen should considerably improve the convenience, efficacy and sideeffect profile of baclofen therapy. However, the rapid passage ofconventional dosage forms through the proximal absorptive region of thesmall intestine has thus far prevented the successful application ofsustained release technologies to this drug. A number of exploratorydelivery technologies that rely on either mucoadhesion or gastricretention have been suggested to achieve sustained delivery of baclofen(Sinnreich, U.S. Pat. No. 4,996,058; Khanna, U.S. Pat. No. 5,091,184;Fara et al., supra; Dudhara et al., International Publication No.WO03/011255) though to date none of these appear to be able to achievesustain blood levels of baclofen in human subjects.

Thus, there is a significant need for new prodrugs of baclofen andbaclofen analogs which are well absorbed in the large intestine/colonand hence suitable for oral sustained release formulations, thusimproving the convenience, efficacy and side effect profile of baclofentherapy.

3. SUMMARY

These and other needs are satisfied by the disclosure herein ofacyloxyalkyl carbamate prodrugs of baclofen and baclofen analogs,pharmaceutical compositions of acyloxyalkyl carbamate prodrugs ofbaclofen and baclofen analogs, methods of making acyloxyalkyl carbamateprodrugs of baclofen and baclofen analogs and methods of usingacyloxyalkyl carbamate prodrugs of baclofen and baclofen analogs and/orpharmaceutical compositions thereof to treat various medical disorders.

In a first aspect, a compound of Formula (I) is provided,

or pharmaceutically acceptable salts, hydrates or solvates thereof,wherein:

R¹ is selected from the group consisting of acyl, substituted acyl,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl;

R² and R³ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl and substituted heteroarylalkyl oroptionally, R² and R³ together with the carbon atom to which they arebonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring;

R⁴ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl or trialkylsilyl; and

R⁵ is selected from the group consisting of substituted aryl, heteroaryland substituted heteroaryl.

In a second aspect, a compound of Formula (II) is provided,

wherein:

X is fluoro, chloro, bromo or iodo; and

R², R³, R⁴ and R⁵ are as defined, supra.

In a third aspect, a method of synthesizing a compound of Formula (I) isprovided, comprising:

contacting a compound of Formula (II), a compound of Formula (III) andat least one equivalent of a metal salt or an organic base or acombination thereof wherein:

X is fluoro, chloro, bromo or iodo; and

R¹, R², R³, R⁴, and R⁵ are as defined, supra.

In a fourth aspect, a method of synthesizing a compound of Formula (I)is provided, comprising contacting a compound of Formula (XVIII) with anoxidant, wherein:

and R¹, R², R³, R⁴, and R⁵ are as defined, supra.

In a fifth aspect, pharmaceutical compositions comprising a compound ofFormula (I), or pharmaceutically acceptable salts, hydrates or solvatesthereof, and a pharmaceutically acceptable vehicle such as a diluent,carrier, excipient or adjuvant are provided. The choice of diluent,carrier, excipient and adjuvant will depend upon, among other factors,the desired mode of administration.

In a sixth aspect, a sustained release oral dosage form, comprising abaclofen prodrug or a baclofen analog prodrug of Formula (I) isprovided, the dosage form being adapted to be swallowed by a patient inorder to introduce the dosage form into an intestinal lumen of thepatient, the dosage form further being adapted to release the baclofenprodrug or a baclofen analog prodrug of Formula (I) gradually into theintestinal lumen of the patient over a period of hours after saidswallowing, said gradual release causing baclofen or the baclofen analogto be cleaved from the promoiety after said swallowing and providing atherapeutic concentration of baclofen or the baclofen analog in theplasma of the patient.

In a seventh aspect, a method of orally administering a baclofen prodrugor a baclofen analog prodrug of Formula (I) is provided, said methodcomprising:

placing a compound of Formula (I) in a sustained release oral dosageform;

introducing the dosage form into the intestinal lumen of a patient byhaving the patient swallow the dosage form;

releasing the prodrug gradually from the swallowed dosage form into theintestinal lumen of the patient over a period of hours; and

allowing baclofen or the baclofen analog to be cleaved from thepromoiety after said swallowing to provide a therapeutic concentrationof the baclofen or baclofen analog in the plasma of the patient.

In an eighth aspect, methods are provided for treating or preventingstiffness, involuntary movements and pain associated with spasticity.Methods are also provided for treating or preventing gastro-esophagealreflux disease, alcohol abuse or addiction, nicotine abuse or addiction,narcotics abuse or addiction, emesis and cough. The methods generallyinvolve administering to a patient in need of such treatment orprevention a therapeutically effective amount of a compound of Formula(I) and/or a pharmaceutical composition thereof.

4. DETAILED DESCRIPTION 4.1 Definitions

“1-Acyloxy-Alkyl Carbamate” refers to an N-1-acyloxy-alkoxycarbonylderivative of baclofen or a baclofen analog as encompassed by compoundsof Formulae (I), (V) and (VI) disclosed herein.

“Alkyl” by itself or as part of another substituent refers to asaturated or unsaturated, branched, straight-chain or cyclic monovalenthydrocarbon radical derived by the removal of one hydrogen atom from asingle carbon atom of a parent alkane, alkene or alkyne. Typical alkylgroups include, but are not limited to, methyl; ethyls such as ethanyl,ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl,cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl,prop-2-yn-1-yl, etc.; butyl s such as butan-1-yl, butan-2-yl,2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl,but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl,but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl,cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl,but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

The term “alkyl” is specifically intended to include groups having anydegree or level of saturation, i.e., groups having exclusively singlecarbon-carbon bonds, groups having one or more double carbon-carbonbonds, groups having one or more triple carbon-carbon bonds and groupshaving mixtures of single, double and triple carbon-carbon bonds. Wherea specific level of saturation is intended, the expressions “alkanyl,”“alkenyl,” and “alkynyl” are used. Preferably, an alkyl group comprisesfrom 1 to 20 carbon atoms, more preferably, from 1 to 10 carbon atoms,most preferably, from 1 to 6 carbon atoms.

“Alkanyl” by itself or as part of another substituent refers to asaturated branched, straight-chain or cyclic alkyl radical derived bythe removal of one hydrogen atom from a single carbon atom of a parentalkane. Typical alkanyl groups include, but are not limited to,methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl(isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl,butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl),2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

“Alkenyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon double bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkene. The groupmay be in either the cis or trans conformation about the double bond(s).Typical alkenyl groups include, but are not limited to, ethenyl;propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl(allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl;butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl,but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl,buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl,cyclobuta-1,3-dien-1-yl, etc.; and the like.

“Alkynyl” by itself or as part of another substituent refers to anunsaturated branched, straight-chain or cyclic alkyl radical having atleast one carbon-carbon triple bond derived by the removal of onehydrogen atom from a single carbon atom of a parent alkyne. Typicalalkynyl groups include, but are not limited to, ethynyl; propynyls suchas prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl,but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

“Acyl” by itself or as part of another substituent refers to a radical—C(O)R³⁰, where R³⁰ is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl,aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl as definedherein. Representative examples include, but are not limited to formyl,acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl,benzylcarbonyl and the like.

“Alkoxy” by itself or as part of another substituent refers to a radical—OR³¹ where R³¹ represents an alkyl or cycloalkyl group as definedherein. Representative examples include, but are not limited to,methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy and the like.

“Alkoxycarbonyl” by itself or as part of another substituent refers to aradical —C(O)OR³¹ where R³¹ represents an alkyl or cycloalkyl group asdefined herein. Representative examples include, but are not limited to,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,cyclohexyloxycarbonyl and the like.

“Aryl” by itself or as part of another substituent refers to amonovalent aromatic hydrocarbon radical derived by the removal of onehydrogen atom from a single carbon atom of a parent aromatic ringsystem. Typical aryl groups include, but are not limited to, groupsderived from aceanthrylene, acenaphthylene, acephenanthrylene,anthracene, azulene, benzene, chrysene, coronene, fluoranthene,fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene,indane, indene, naphthalene, octacene, octaphene, octalene, ovalene,penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene,phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene,triphenylene, trinaphthalene and the like. Preferably, an aryl groupcomprises from 6 to 20 carbon atoms, more preferably, from 6 to 12carbon atoms.

“Arylalkyl” by itself or as part of another substituent refers to anacyclic alkyl radical in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp³ carbon atom, is replaced withan aryl group. Typical arylalkyl groups include, but are not limited to,benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl,2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. Where specific alkyl moietiesare intended, the nomenclature arylalkanyl, arylalkenyl and/orarylalkynyl is used. Preferably, an arylalkyl group is (C₇-C₃₀)arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkylgroup is (C₁-C₁₀) and the aryl moiety is (C₆-C₂₀), more preferably, anarylalkyl group is (C₇-C₂₀) arylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the arylalkyl group is (C₁-C₈) and the aryl moiety is(C₆-C₁₂).

“Aryldialkylsilyl” by itself or as part of another substituent refers tothe radical SiR³²R³³R³⁴ where one of R³², R³³ or R³⁴ is aryl as definedherein and the other two of R³², R³³ or R³⁴ are alkyl as defined herein.

“AUC” is the area under the plasma drug concentration-versus-time curveextrapolated from zero time to infinity.

“C_(max)” is the highest drug concentration observed in plasma followingan extravascular dose of drug.

“Compounds” refers to compounds encompassed by structural formulae(I)-(XXIII) disclosed herein and includes any specific compounds withinthese formulae whose structure is disclosed herein. Compounds may beidentified either by their chemical structure and/or chemical name. Whenthe chemical structure and chemical name conflict, the chemicalstructure is determinative of the identity of the compound. Thecompounds described herein may contain one or more chiral centers and/ordouble bonds and therefore, may exist as stereoisomers, such asdouble-bond isomers (i.e., geometric isomers), enantiomers ordiastereomers. Accordingly, the chemical structures depicted hereinencompass all possible enantiomers and stereoisomers of the illustratedcompounds including the stereoisomerically pure form (e.g.,geometrically pure, enantiomerically pure or diastereomerically pure)and enantiomeric and stereoisomeric mixtures. Enantiomeric andstereoisomeric mixtures can be resolved into their component enantiomersor stereoisomers using separation techniques or chiral synthesistechniques well known to the skilled artisan. The compounds may alsoexist in several tautomeric forms including the enol form, the keto formand mixtures thereof. Accordingly, the chemical structures depictedherein encompass all possible tautomeric forms of the illustratedcompounds. The compounds described also include isotopically labeledcompounds where one or more atoms have an atomic mass different from theatomic mass conventionally found in nature. Examples of isotopes thatmay be incorporated into the compounds disclosed herein include, but arenot limited to, ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, etc. Compounds mayexist in unsolvated forms as well as solvated forms, including hydratedforms and as N-oxides. In general, compounds may be hydrated, solvatedor N-oxides. Certain compounds may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated herein and are intended to be within the scope of thepresent disclosure. Further, it should be understood, when partialstructures of the compounds are illustrated, that brackets indicate thepoint of attachment of the partial structure to the rest of themolecule.

“Cycloalkoxycarbonyl” by itself or as part of another substituent refersto a radical —C(O)OR³⁶ where R³⁶ represents an cycloalkyl group asdefined herein. Representative examples include, but are not limited to,cyclobutyloxycarbonyl, cyclohexyloxycarbonyl and the like.

“Cycloalkyl” by itself or as part of another substituent refers to asaturated or unsaturated cyclic alkyl radical. Where a specific level ofsaturation is intended, the nomenclature “cycloalkanyl” or“cycloalkenyl” is used. Typical cycloalkyl groups include, but are notlimited to, groups derived from cyclopropane, cyclobutane, cyclopentane,cyclohexane and the like. Preferably, the cycloalkyl group is (C₃-C₁₀)cycloalkyl, more preferably (C₃-C₇) cycloalkyl.

“Cycloheteroalkyl” by itself or as part of another substituent refers toa saturated or unsaturated cyclic alkyl radical in which one or morecarbon atoms (and any associated hydrogen atoms) are independentlyreplaced with the same or different heteroatom. Typical heteroatoms toreplace the carbon atom(s) include, but are not limited to, N, P, O, S,Si, etc. Where a specific level of saturation is intended, thenomenclature “cycloheteroalkanyl” or “cycloheteroalkenyl” is used.Typical cycloheteroalkyl groups include, but are not limited to, groupsderived from epoxides, azirines, thiiranes, imidazolidine, morpholine,piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine and thelike.

“1-Haloalkyl Carbamate” refers to an N-1-haloalkoxycarbonyl derivativeof baclofen or a baclofen analog as encompassed by compounds of Formulae(II), (VII) and (VIII) disclosed herein.

“Heteroalkyl. Heteroalkanyl, Heteroalkenyl and Heteroalkynyl” bythemselves or as part of another substituent refer to alkyl, alkanyl,alkenyl and alkynyl groups, respectively, in which one or more of thecarbon atoms (and any associated hydrogen atoms) are independentlyreplaced with the same or different heteroatomic groups. Typicalheteroatomic groups which can be included in these groups include, butare not limited to, —O—, —S—, —O—O—, —S—S—, —O—S—, —NR³⁷R³⁸—, ═N—N═,—N═N—, —N═N—NR³⁹R⁴⁰, —PR⁴¹—, POR⁴²—, —O—P(O)₂—, —SO—, —SO₂—, —SnR⁴³R⁴⁴—and the like, where R³⁷, R³⁸, R³⁹, R⁴⁰, R⁴¹, R⁴², R⁴³ and R⁴⁴ areindependently hydrogen, alkyl, substituted alkyl, aryl, substitutedaryl, arylalkyl, substituted arylalkyl, cycloalkyl, substitutedcycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl,substituted heteroalkyl, heteroaryl, substituted heteroaryl,heteroarylalkyl or substituted heteroarylalkyl.

“Heteroaryl” by itself or as part of another substituent, refers to amonovalent heteroaromatic radical derived by the removal of one hydrogenatom from a single atom of a parent heteroaromatic ring system. Typicalheteroaryl groups include, but are not limited to, groups derived fromacridine, arsindole, carbazole, β-carboline, chromane, chromene,cinnoline, furan, imidazole, indazole, indole, indoline, indolizine,isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine,pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and thelike. Preferably, the heteroaryl group is from 5-20 membered heteroaryl,more preferably from 5-10 membered heteroaryl. Preferred heteroarylgroups are those derived from thiophene, pyrrole, benzothiophene,benzofuran, indole, pyridine, quinoline, imidazole, oxazole andpyrazine.

“Heteroarylalkyl” by itself or as part of another substituent refers toan acyclic alkyl radical in which one of the hydrogen atoms bonded to acarbon atom, typically a terminal or sp^(a) carbon atom, is replacedwith a heteroaryl group. Where specific alkyl moieties are intended, thenomenclature heteroarylalkanyl, heteroarylalkenyl and/orheterorylalkynyl is used. In preferred embodiments, the heteroarylalkylgroup is a 6-30 membered heteroarylalkyl, e.g., the alkanyl, alkenyl oralkynyl moiety of the heteroarylalkyl is 1-10 membered and theheteroaryl moiety is a 5-20-membered heteroaryl, more preferably, 6-20membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moietyof the heteroarylalkyl is 1-8 membered and the heteroaryl moiety is a5-12-membered heteroaryl.

“Parent Aromatic Ring System” refers to an unsaturated cyclic orpolycyclic ring system having a conjugated π electron system.Specifically included within the definition of “parent aromatic ringsystem” are fused ring systems in which one or more of the rings arearomatic and one or more of the rings are saturated or unsaturated, suchas, for example, fluorene, indane, indene, phenalene, etc. Typicalparent aromatic ring systems include, but are not limited to,aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene,trinaphthalene and the like.

“Parent Heteroaromatic Ring System” refers to a parent aromatic ringsystem in which one or more carbon atoms (and any associated hydrogenatoms) are independently replaced with the same or different heteroatom.Typical heteroatoms to replace the carbon atoms include, but are notlimited to, N, P, O, S, Si, etc. Specifically included within thedefinition of “parent heteroaromatic ring systems” are fused ringsystems in which one or more of the rings are aromatic and one or moreof the rings are saturated or unsaturated, such as, for example,arsindole, benzodioxan, benzofuran, chromane, chromene, indole,indoline, xanthene, etc. Typical parent heteroaromatic ring systemsinclude, but are not limited to, arsindole, carbazole, β-carboline,chromane, chromene, cinnoline, furan, imidazole, indazole, indole,indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like.

“Pharmaceutical composition” refers to at least one compound and apharmaceutically acceptable vehicle, with which the compound isadministered to a patient.

“Pharmaceutically acceptable salt” refers to a salt of a compound, whichpossesses the desired pharmacological activity of the parent compound.Such salts include: (1) acid addition salts, formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound isreplaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound sis administered.

“Patient” includes humans. The terms “human” and “patient” are usedinterchangeably herein.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a patient that may be exposedto or predisposed to the disease but does not yet experience or displaysymptoms of the disease).

“Prodrug” refers to a derivative of a drug molecule that requires atransformation within the body to release the active drug. Prodrugs arefrequently, although not necessarily, pharmacologically inactive untilconverted to the parent drug.

“Promoiety” refers to a form of protecting group that when used to maska functional group within a drug molecule converts the drug into aprodrug. Typically, the promoiety will be attached to the drug viabond(s) that are cleaved by enzymatic or non-enzymatic means in vivo.

“Protecting group” refers to a grouping of atoms that when attached to areactive functional group in a molecule masks, reduces or preventsreactivity of the functional group. Examples of protecting groups can befound in Green et al., “Protective Groups in Organic Chemistry”, (Wiley,2^(nd) ed. 1991) and Harrison et al., “Compendium of Synthetic OrganicMethods”, Vols. 1-8 (John Wiley and Sons, 1971-1996). Representativeamino protecting groups include, but are not limited to, formyl, acetyl,trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl(“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl(“SES”), trityl and substituted trityl groups, allyloxycarbonyl,9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl(“NVOC”) and the like. Representative hydroxy protecting groups include,but are not limited to, those where the hydroxy group is either acylatedor alkylated such as benzyl, and trityl ethers as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers and allyl ethers.

“Substantially one diastereomer” refers to a compound containing 2 ormore stereogenic centers such that the diastereomeric excess (d.e.) ofthe compound is greater than or at least 90%. In some embodiments, thed.e. is, for example, greater than or at least 91%, 92%, 93%, 94%, 95%,96%, 97%, 98% or 99%.

“Substituted” refers to a group in which one or more hydrogen atoms areindependently replaced with the same or different substituent(s).Typical substituents include, but are not limited to, -M, —R⁶⁰, —O—, ═O,—OR⁶⁰, —SR⁶⁰, —S⁻, ═S, —NR⁶⁰R⁶¹, ═NR⁶⁰, —CF₃, —CN, —OCN, —SCN, —NO,—NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)₂R⁶⁰, —OS(O₂)O⁻, —OS(O)₂R⁶⁰,—P(O)(O⁻)₂, —P(O)(OR⁶⁰)(O)⁻, —OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(S)R⁶⁰,—C(O)OR⁶⁰, —C(O)NR⁶⁰R⁶¹, —C(O)O⁻, —C(S)OR⁶⁰, —NR⁶²C(O)NR⁶⁰R⁶¹,—NR⁶²C(S)NR⁶⁰R⁶¹, —NR⁶²C(NR⁶³)NR⁶⁰R⁶¹ and —C(NR⁶²)NR⁶⁰R⁶¹ where M isindependently a halogen; R⁶⁰, R⁶¹, R⁶² and R⁶³ are independentlyhydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, aryl, substituted aryl, heteroaryl or substitutedheteroaryl, or optionally R⁶⁰ and R⁶¹ together with the nitrogen atom towhich they are bonded form a cycloheteroalkyl or substitutedcycloheteroalkyl ring; and R⁶⁴ and R⁶⁵ are independently hydrogen,alkyl, substituted alkyl, aryl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, aryl, substituted aryl,heteroaryl or substituted heteroaryl, or optionally R⁶⁴ and R⁶⁵ togetherwith the nitrogen atom to which they are bonded form a cycloheteroalkylor substituted cycloheteroalkyl ring. Preferably, substituents include-M, —R⁶⁰, ═O, —OR⁶⁰, —SR⁶⁰, —S⁻, ═S, —NR⁶⁰R⁶¹, ═NR⁶⁰, —CF₃, —CN, —OCN,—SCN, —NO, —NO₂, ═N₂, —N₃, —S(O)₂R⁶⁰, —OS(O₂)O⁻, —OS(O)₂R⁶⁰, —P(O)(O)₂,—P(O)(OR⁶⁰)(O⁻), —OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(s)R⁶⁰, C(O)OR⁶⁰,—C(O)NR⁶⁰R⁶¹, —C(O)O⁻, —NR⁶²C(O)NR⁶⁰R⁶¹, more preferably, -M, —R⁶⁰, ═O,—OR⁶⁰, —SR⁶⁰, —NR⁶⁰R⁶¹, —CF₃, —CN, —NO₂, —S(O)₂R⁶⁰)(O⁻),—P(O)(OR⁶⁰)(O⁻), —OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)NR⁶⁰R⁶¹,—C(O)O⁻, most preferably, -M, —R⁶⁰, ═O, —OR⁶⁰, —SR⁶⁰, —NR⁶⁰R⁶¹, —CF₃,—CN, —NO₂, —S(O)₂R⁶⁰, —OP(O)(OR⁶⁰)(OR⁶¹), —C(O)R⁶⁰, —C(O)OR⁶⁰, —C(O)O⁻,where R⁶⁰, R⁶¹ and R⁶² are as defined above.

“Treating” or “treatment” of any disease or disorder refers, in someembodiments, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In other embodiments “treating” or “treatment” refersto ameliorating at least one physical parameter, which may not bediscernible by the patient. In yet other embodiments, “treating” or“treatment” refers to inhibiting the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In still other embodiments, “treating” or “treatment” refers to delayingthe onset of the disease or disorder.

“Therapeutically effective amount” means the amount of a compound that,when administered to a patient for treating a disease, is sufficient toeffect such treatment for the disease. The “therapeutically effectiveamount” will vary depending on the compound, the disease and itsseverity and the age, weight, etc., of the patient to be treated.

“Trialkylsilyl” by itself or as part of another substituent refers to aradical —SiR⁵⁰R⁵¹R⁵² where R⁵⁰, R⁵¹ and R⁵² are alkyl as defined herein.

Reference will now be made in detail to particular embodiments ofcompounds and methods. The disclosed embodiments are not intended to belimiting of the claims. To the contrary, is the claims are intended tocover all alternatives, modifications and equivalents.

4.2 Compounds

In a first aspect, a compound of Formula (I) is provided,

or pharmaceutically acceptable salts, hydrates or solvates thereof,wherein:

R¹ is selected from the group consisting of acyl, substituted acyl,alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl;

R² and R³ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl and substituted heteroarylalkyl oroptionally, R² and R³ together with the carbon atom to which they arebonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring;

R⁴ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl or trialkylsilyl; and

R⁵ is selected from the group consisting of substituted aryl, heteroaryland substituted heteroaryl.

In some embodiments, R⁵ is selected from the group consisting of4-chlorophenyl, (3R)-4-chlorophenyl, 2-chlorophenyl, 4-fluorophenyl,thien-2-yl; 5-chlorothien-2-yl, 5-bromothien-2-yl, 5-methylthien-2-yland 2-imidazolyl. In other embodiments, R⁵ is selected from the groupconsisting of -chlorophenyl, (3R)-4-chlorophenyl, 2-chlorophenyl,4-fluorophenyl.

In still other embodiments, the compound of Formula (I) has thestructure of Formula (V):

or pharmaceutically acceptable salts, hydrates or solvates thereof;

wherein:

R¹, R², R³ and R⁴ are as defined, supra.

In still other embodiments, a compound of Formula (I), has the structureof Formula (VI):

or pharmaceutically acceptable salts, hydrates or solvates thereof;

wherein R¹, R², R³ and R⁴ are as defined, supra.

In some embodiments of compounds of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl. In other embodiments of compounds of Formulae (I), (V) or (VI),R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl, 4-methoxyphenyl, benzyl,phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,2-pyridyl, 3-pyridyl or 4-pyridyl. In still other embodiments ofcompounds of Formulae (I), (V) or (VI), R¹ is methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl, cyclohexylor 3-pyridyl.

In still other embodiments of compounds of Formulae (I), (V) or (VI), R²and R³ are independently selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl,aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl,cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substitutedcycloalkoxycarbonyl, heteroaryl, substituted heteroaryl, heteroarylalkyland substituted heteroarylalkyl. In still other embodiments of compoundsof Formulae (I), (V) or (VI), R² and R³ are independently selected fromthe group consisting of hydrogen, C₁₋₄ alkyl, substituted C₁ alkyl, C₁₋₄alkoxycarbonyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxycarbonyl, phenyl,substituted phenyl, C₇₋₉ phenylalkyl and pyridyl. In still otherembodiments of compounds of Formulae (I), (V) or (VI), R² and R³ areindependently selected from the group consisting of hydrogen, methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl,2-pyridyl, 3-pyridyl and 4-pyridyl. In still other embodiments ofcompounds of Formulae (I), (V) or (VI), R² is hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl,2-pyridyl, 3-pyridyl or 4-pyridyl and R³ is hydrogen. In still otherembodiments of compounds of Formulae (I), (V) or (VI), R² is hydrogen,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenylor cyclohexyl and R³ is hydrogen. In still other embodiments of acompound of Formulae (I), (V) or (VI), R² is methyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl or cyclohexyloxycarbonyl, and R³ ismethyl.

In still other embodiments of a compound of Formulae (I), (V) or (VI),R² and R³ together with the carbon atom to which they are attached forma cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substitutedcycloheteroalkyl ring. In still other embodiments of compounds ofFormulae (I), (V) or (VI), R² and R³ together with the carbon atom towhich they are attached form a cyclobutyl, cyclopentyl or cyclohexylring.

In still other embodiments of a compound of Formulae (I), (V) or (VI),R⁴ is selected from the group consisting of hydrogen, C₁₋₆ alkyl,substituted C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl,C₇₋₉ phenylalkyl, substituted C₇₋₉ phenylalkyl, trialkylsilyl andaryldialkylsilyl. In still other embodiments of a compound of Formulae(I), (V) or (VI), R⁴ is hydrogen, methyl, ethyl, tert-butyl, allyl,benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylmethyl,trimethylsilyl, triethylsilyl, triisopropylsilyl,tert-butyldimethylsilyl or phenyldimethylsilyl. In still otherembodiments of a compound of Formulae (I), (V) or (VI), R⁴ is hydrogen,allyl, benzyl or trimethylsilyl. In still other embodiments of acompound of Formulae (I), (V) or (VI), R⁴ is hydrogen.

In some embodiments of a compound of Formula (I), R⁵ is substitutedaryl. In other embodiments of a compound of Formula (I), R⁵ issubstituted phenyl. In still other embodiments, R⁵ is phenyl substitutedwith one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² and R³ are independently selected from the group consistingof hydrogen, C₁₋₄ alkyl, substituted C₁₋₄ alkyl, C₁₋₄ alkoxycarbonyl,C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxycarbonyl, phenyl, substituted phenyl,C₇₋₉ phenylalkyl and pyridyl and R⁴ is selected from the groupconsisting of hydrogen, C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl, substitutedC₇₋₉ phenylalkyl, trialkylsilyl and aryldialkylsilyl. Preferably, in theabove embodiments, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, morepreferably, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl or 3-pyridyl. In the aboveembodiments of a compound of Formula (I), R⁵ is preferably substitutedaryl, more preferably, substituted phenyl, most preferably, phenylsubstituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² and R³ are independently selected from the group consistingof hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl,benzyl, phenethyl, 2-pyridyl, 3-pyridyl and 4-pyridyl and R⁴ is selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl,substituted C₇₋₉ phenylalkyl, trialkylsilyl and aryldialkylsilyl.Preferably, in the above embodiments, R¹ is methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl or 4-pyridyl,more preferably, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-diethoxyethyl, phenyl, cyclohexyl or 3-pyridyl. In theabove embodiments of a compound of Formula (I), R⁵ is preferablysubstituted aryl, more preferably, substituted phenyl, most preferably,phenyl substituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, phenyl or cyclohexyl, R³ is hydrogen and R⁴ isselected from the group consisting of hydrogen, C₁₋₆ alkyl, substitutedC₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉phenylalkyl, substituted C₇₋₉ phenylalkyl, trialkylsilyl andaryldialkylsilyl. Preferably, in the above embodiments, R¹ is methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridylor 4-pyridyl, more preferably, R¹ is methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl, cyclohexyl or3-pyridyl. In the above embodiments of a compound of Formula (I), R⁵ ispreferably substituted aryl, more preferably, substituted phenyl, mostpreferably, phenyl substituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² is methyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl or cyclohexyloxycarbonyl, R³ is methyl and R⁴ is selected fromthe group consisting of hydrogen, C₁₋₆ alkyl, substituted C₁₋₆ alkyl,C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl,substituted C₇₋₉ phenylalkyl, trialkylsilyl and aryldialkylsilyl.Preferably, in the above embodiments, R¹ is methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl or 4-pyridyl,more preferably, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-diethoxyethyl, phenyl, cyclohexyl or 3-pyridyl. In theabove embodiments of a compound of Formula (I), R⁵ is preferablysubstituted aryl, more preferably, substituted phenyl, most preferably,phenyl substituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² and R³ are independently selected from the group consistingof hydrogen, C₁₋₄ alkyl, substituted C₁₋₄ alkyl, C₁₋₄ alkoxycarbonyl,C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxycarbonyl, phenyl, substituted phenyl,C₇₋₉ phenylalkyl and pyridyl and R⁴ is hydrogen, methyl, ethyl,tert-butyl, allyl, benzyl, 4-methoxybenzyl, diphenylmethyl,triphenylmethyl, trimethylsilyl, triisopropylsilyl,tert-butyldimethylsilyl or phenyldimethylsilyl. Preferably, in the aboveembodiments, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, morepreferably, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl or 3-pyridyl. In the aboveembodiments of a compound of Formula (I), R⁵ is preferably substitutedaryl, more preferably, substituted phenyl, most preferably, phenylsubstituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² and R³ are independently selected from the group consistingof hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl,benzyl, phenethyl, 2-pyridyl, 3-pyridyl and 4-pyridyl and R⁴ ishydrogen, methyl, ethyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl,diphenylmethyl, triphenylmethyl, trimethylsilyl, triisopropylsilyl,tert-butyldimethylsilyl or phenyldimethylsilyl. Preferably, in the aboveembodiments, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, morepreferably, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl or 3-pyridyl. In the aboveembodiments of a compound of Formula (I), R⁵ is preferably substitutedaryl, more preferably, substituted phenyl, most preferably, phenylsubstituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, phenyl or cyclohexyl, R³ is hydrogen and R⁴ ishydrogen, methyl, ethyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl,diphenylmethyl, triphenylmethyl, trimethylsilyl, triisopropylsilyl,tert-butyldimethylsilyl or phenyldimethylsilyl. Preferably, in the aboveembodiments, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, morepreferably, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl or 3-pyridyl. In the aboveembodiments of a compound of Formula (I), R⁵ is preferably substitutedaryl, more preferably, substituted phenyl, most preferably, phenylsubstituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² is methyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl or cyclohexyloxycarbonyl, R³ is methyl and R⁴ ishydrogen, methyl, ethyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl,diphenylmethyl, triphenylmethyl, trimethylsilyl, triisopropylsilyl,tert-butyldimethylsilyl or phenyldimethylsilyl. Preferably, in the aboveembodiments, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, morepreferably, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl or 3-pyridyl. In the aboveembodiments of a compound of Formula (I), R⁵ is preferably substitutedaryl, more preferably, substituted phenyl, most preferably, phenylsubstituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² and R³ are independently selected from the group consistingof hydrogen, C₁₋₄ alkyl, substituted C₁₋₄ alkyl, C₁₋₄ alkoxycarbonyl,C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxycarbonyl, phenyl, substituted phenyl,C₇₋₉ phenylalkyl and pyridyl and R⁴ is hydrogen, allyl, benzyl ortrimethylsilyl. Preferably, in the above embodiments, R¹ is methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl,1,1-diethoxyethyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridylor 4-pyridyl, more preferably, R¹ is methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl,sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl, cyclohexyl or3-pyridyl. In the above embodiments of a compound of Formula (I), R⁵ ispreferably substituted aryl, more preferably, substituted phenyl, mostpreferably, phenyl substituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² and R³ are independently selected from the group consistingof hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl,benzyl, phenethyl, 2-pyridyl, 3-pyridyl and 4-pyridyl and R⁴ ishydrogen, allyl, benzyl or trimethylsilyl. Preferably, in the aboveembodiments, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, morepreferably, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl or 3-pyridyl. In the aboveembodiments of a compound of Formula (I), R⁵ is preferably substitutedaryl, more preferably, substituted phenyl, most preferably, phenylsubstituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, phenyl or cyclohexyl, R³ is hydrogen and R⁴ ishydrogen, allyl, benzyl or trimethylsilyl. Preferably, in the aboveembodiments, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, morepreferably, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl or 3-pyridyl. In the aboveembodiments of a compound of Formula (I), R⁵ is preferably substitutedaryl, more preferably, substituted phenyl, most preferably, phenylsubstituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² is methyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl or cyclohexyloxycarbonyl, R³ is methyl and R⁴ ishydrogen, allyl, benzyl or trimethylsilyl. Preferably, in the aboveembodiments, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, morepreferably, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl or 3-pyridyl. In the aboveembodiments of a compound of Formula (I), R⁵ is preferably substitutedaryl, more preferably, substituted phenyl, most preferably, phenylsubstituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² and R³ are independently selected from the group consistingof hydrogen, C₁₋₄ alkyl, substituted C₁₋₄ alkyl, C₁₋₄ alkoxycarbonyl,C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxycarbonyl, phenyl, substituted phenyl,C₇₋₉ phenylalkyl and pyridyl and R⁴ is hydrogen. Preferably, in theabove embodiments, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, phenyl,4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, morepreferably, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl or 3-pyridyl. In the aboveembodiments of a compound of Formula (I), R⁵ is preferably substitutedaryl, more preferably, substituted phenyl, most preferably, phenylsubstituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² and R³ are independently selected from the group consistingof hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl,benzyl, phenethyl, 2-pyridyl, 3-pyridyl and 4-pyridyl and R⁴ ishydrogen. Preferably, in the above embodiments, R¹ is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl or 4-pyridyl,more preferably, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-diethoxyethyl, phenyl, cyclohexyl or 3-pyridyl. In theabove embodiments of a compound of Formula (I), R⁵ is preferablysubstituted aryl, more preferably, substituted phenyl, most preferably,phenyl substituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, phenyl or cyclohexyl, R³ is hydrogen and R⁴ ishydrogen. Preferably, in the above embodiments, R¹ is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl or 4-pyridyl,more preferably, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-diethoxyethyl, phenyl, cyclohexyl or 3-pyridyl. In theabove embodiments of a compound of Formula (I), R⁵ is preferablysubstituted aryl, more preferably, substituted phenyl, most preferably,phenyl substituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ isselected from the group consisting of C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl andpyridyl, R² is methyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl or cyclohexyloxycarbonyl, R³ is methyl and R⁴ ishydrogen. Preferably, in the above embodiments, R¹ is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl or 4-pyridyl,more preferably, R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl,neopentyl, 1,1-diethoxyethyl, phenyl, cyclohexyl or 3-pyridyl. In theabove embodiments of a compound of Formula (I), R⁵ is preferablysubstituted aryl, more preferably, substituted phenyl, most preferably,phenyl substituted with one or more halogen atoms.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ ismethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl or4-pyridyl, R² is hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, phenyl or cyclohexyl, R³ is hydrogen and R⁴ ishydrogen. In other embodiments of compounds of Formulae (I), (V) or(VI), R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl or4-pyridyl, R² is hydrogen, methyl, n-propyl, or isopropyl, R³ ishydrogen and R⁴ is hydrogen. In still other embodiments of compounds ofFormulae (I), (V) or (VI), R¹ is methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl or3-pyridyl, R² is hydrogen, methyl, n-propyl, or isopropyl, R³ ishydrogen and R⁴ is hydrogen.

In still other embodiments of compounds of Formulae (I), (V) or (VI), R¹is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, n-pentyl, isopentyl, sec-pentyl, neopentyl,1,1-diethoxyethyl, phenyl, cyclohexyl, 2-pyridyl, 3-pyridyl or4-pyridyl, R² is methyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl or cyclohexyloxycarbonyl, R³ is methyl and R⁴ ishydrogen.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ ismethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl or 3-pyridyl, R² is hydrogen, R³ ishydrogen and R⁴ is hydrogen. In other embodiments of a compound ofFormulae (I), (V) or (VI), R¹ is methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl or3-pyridyl, R² is methyl, R³ is hydrogen and R⁴ is hydrogen. In yet otherembodiments of a compound of Formulae (I), (V) or (VI), R¹ is methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,phenyl, cyclohexyl or 3-pyridyl, R² is n-propyl, R³ is hydrogen and R⁴is hydrogen. In still other embodiments of a compound of Formulae (I),(V) or (VI), R¹ is methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl or 3-pyridyl, R² isisopropyl, R³ is hydrogen and R⁴ is hydrogen.

In some embodiments of a compound of Formula (I), R² and R³ aredifferent and the compound of Formula (I) is substantially onediastereomer. In other embodiments of a compound of Formula (I), thestereochemistry at the carbon to which R² and R³ are attached is of theS-configuration and the compound of Formula (I) is substantially onediastereomer. In still other embodiments of a compound of Formula (I),the stereochemistry at the carbon to which R² and R³ are attached is ofthe R-configuration, and the compound of Formula (I) is substantiallyone diastereomer. In some embodiments of a compound of Formula (I), R²is C₁₋₄ alkyl, R³ is hydrogen and the compound of Formula (I) issubstantially one diastereomer. In other embodiments of a compound ofFormula (I), R² is C₁₋₄ alkyl, R³ is hydrogen, the stereochemistry atthe carbon to which R² and R³ are attached is of the S-configuration andthe compound of Formula (I) is substantially one diastereomer. In otherembodiments of a compound of Formula (I), R² is C₁₋₄ alkyl, R³ ishydrogen, the stereochemistry at the carbon to which R² and R³ areattached is of the R-configuration, and the compound of Formula (I) issubstantially one diastereomer.

In some embodiments of a compound of Formula (VI), R² and R³ in thecompound of Formula (VI) are different and the compound of Formula (VI)is substantially one diastereomer. In other embodiments of a compound ofFormula (VI), the stereochemistry at the carbon to which R² and R³ areattached is of the S-configuration and the compound of Formula (VI) issubstantially one diastereomer. In other embodiments of a compound ofFormula (VI), the stereochemistry at the carbon to which R² and R³ areattached is of the R-configuration and the compound of Formula (VI) issubstantially one diastereomer. In still other embodiments of a compoundof Formula (VI), R² is C₁₋₄ alkyl, R³ is hydrogen, and the compound ofFormula (VI) is substantially one diastereomer. In still otherembodiments of a compound of Formula (VI), R² is C₁₋₄ alkyl, R³ ishydrogen, the stereochemistry at the carbon to which R² and R³ areattached is of the S-configuration, and the compound of Formula (VI) issubstantially one diastereomer. In still other embodiments of a compoundof Formula (VI), R² is C₁₋₄ alkyl, R³ is hydrogen, the stereochemistryat the carbon to which R² and R³ are attached is of the R-configuration,and the compound of Formula (VI) is substantially one diastereomer.

In some embodiments of a compound of Formulae (I), (V) or (VI), R¹ ismethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl or 3-pyridyl, R² is methyl, R³ ishydrogen, R⁴ is hydrogen, the stereochemistry at the carbon to which R²and R³ are attached is of the S-configuration and the compound ofFormulae (I), (V) or (VI) is substantially one diastereomer. In otherembodiments of a compound of Formulae (I), (V) or (VI), R¹ is methyl,ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,phenyl, cyclohexyl or 3-pyridyl, R² is methyl, R³ is hydrogen, R⁴ ishydrogen, the stereochemistry at the carbon to which R² and R³ areattached is of the R-configuration and the compound of Formulae (I), (V)or (VI), is substantially one diastereomer. In still other embodimentsof a compound of Formulae (I), (V) or (VI), R¹ is methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl,cyclohexyl or 3-pyridyl, R² is n-propyl, R³ is hydrogen, R⁴ is hydrogen,the stereochemistry at the carbon to which R² and R³ are attached is ofthe S-configuration, and the compound of Formulae (I), (V) or (VI), issubstantially one diastereomer. In still other embodiments of a compoundof Formulae (I), (V) or (VI), R¹ is methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl or3-pyridyl, R² is n-propyl, R³ is hydrogen, R⁴ is hydrogen, thestereochemistry at the carbon to which R² and R³ are attached is of theR-configuration, and the compound of Formulae (I), (V) or (VI) issubstantially one diastereomer. In still other embodiments of a compoundof Formulae (I), (V) or (VI), R¹ is methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl or3-pyridyl, R² is isopropyl, R³ is hydrogen, R⁴ is hydrogen, thestereochemistry at the carbon to which R² and R³ are attached is of theS-configuration and the compound of Formulae (I), (V) or (VI) issubstantially one diastereomer. In other embodiments of a compound ofFormulae (I), (V) or (VI), R¹ is methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, phenyl, cyclohexyl or3-pyridyl, R² is isopropyl, R³ is hydrogen, R⁴ is hydrogen, thestereochemistry at the carbon to which R² and R³ are attached is of theR-configuration and the compound of Formulae (I), (V) or (VI), issubstantially one diastereomer. In still other embodiments of a compoundof Formulae (I), (V) or (VI), R¹ is isopropyl, R² is isopropyl, R³ ishydrogen, R⁴ is hydrogen, the stereochemistry at the carbon to which R²and R³ are attached is of the S-configuration, and the compound ofFormulae (I), (V) or (VI) is substantially one diastereomer. In stillother embodiments of a compound of Formulae (I), (V) or (VI), R¹ isisopropyl, R² is isopropyl, R³ is hydrogen, R⁴ is hydrogen, thestereochemistry at the carbon to which R² and R³ are attached is of theR-configuration, and the compound of Formulae (I), (V) or (VI) issubstantially one diastereomer.

In another aspect, a compound of Formula (II) is provided,

wherein:

X is fluoro, chloro, bromo or iodo;

R² and R³ are independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl and substituted heteroarylalkyl oroptionally, R² and R³ together with the carbon atom to which they arebonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring;

R⁴ is selected from the group consisting of hydrogen, alkyl, substitutedalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl,aryldialkylsilyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl or trialkylsilyl; and

R⁵ is selected from the group consisting of substituted aryl, heteroaryland substituted heteroaryl.

In some embodiments, R⁵ is selected from the group consisting of4-chlorophenyl; R-(4-chlorophenyl), 2-chlorophenyl), 4-fluorophenyl,thien-2-yl, 5-chlorothien-2-yl, 5-bromothien-2-yl and5-methylthien-2-yl.

In other embodiments, the compound of Formula (II) has the structure ofFormula (VII):

or pharmaceutically acceptable salts, hydrates or solvates thereof;

wherein:

X, R², R³ and R⁴ are as previously defined, supra.

In still other embodiments, the compound of Formula (II) has thestructure of Formula (VIII):

or pharmaceutically acceptable salts, hydrates or solvates thereof;

wherein:

X, R², R³ and R⁴ are as previously defined, supra.

In some embodiments of a compound of Formulae (II), (VII) or (VIII), Xis chloro, bromo or iodo. In other embodiments of a compound of Formulae(II), (VII) or (VIII), X is chloro.

In still other embodiments of a compound of Formulae (II), (VII) or(VIII), R² and R³ are independently selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substitutedalkoxycarbonyl, aryl, substituted aryl, arylalkyl, substitutedarylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl,cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl,substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl.In still other embodiments of a compound of Formulae (II), (VII) or(VIII), R² and R³ are independently selected from the group consistingof hydrogen, C₁₋₄ alkyl, substituted C₁₋₄ alkyl, C₁₋₄ alkoxycarbonyl,C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxycarbonyl, phenyl, substituted phenyl,C₇₋₉ phenylalkyl and pyridyl. In still other embodiments of a compoundof Formulae (II), (VII) or (VIII), R² and R³ are independently selectedfrom the group consisting of hydrogen, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl,cyclohexyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl,cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl, 2-pyridyl, 3-pyridyland 4-pyridyl. In still other embodiments of a compound of Formulae(II), (VII) or (VIII), R² is hydrogen, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, phenyl or cyclohexyl and R³ ishydrogen. In still other embodiments of a compound of Formulae (II),(VII) or (VIII), R² is methyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl or cyclohexyloxycarbonyl and R³ is methyl.

In still other embodiments of a compound of Formulae (II), (VII) or(VIII), R² and R³ together with the carbon atom to which they areattached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl orsubstituted cycloheteroalkyl ring. In still other embodiments of acompound of Formulae (II), (VII) or (VIII), R² and R³ together with thecarbon atom to which they are attached form a cyclobutyl, cyclopentyl orcyclohexyl ring.

In still other embodiments of a compound of Formulae (II), (VII) or(VIII), R⁴ is selected from the group consisting of hydrogen, C₁₋₆alkyl, substituted C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, substitutedphenyl, C₇₋₉ phenylalkyl, substituted C₇₋₉ phenylalkyl, trialkylsilyland aryldialkylsilyl. In still other embodiments of a compound ofFormulae (II), (VII) or (VIII), R⁴ is hydrogen, methyl, ethyl,tert-butyl, allyl, benzyl, 4-methoxybenzyl, diphenylmethyl,triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl,tert-butyldimethylsilyl or phenyldimethylsilyl. In still otherembodiments of a compound of Formulae (II), (VII) or (VIII), R⁴ ishydrogen, allyl, benzyl or trimethylsilyl.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² and R³ are independently selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl, substituted C₁₋₄alkyl, C₁₋₄ alkoxycarbonyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxycarbonyl,phenyl, substituted phenyl, C₇₋₉ phenylalkyl and pyridyl and R⁴ isselected from the group consisting of hydrogen, C₁₋₆ alkyl, substitutedC₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉phenylalkyl, substituted C₇₋₉ phenylalkyl, trialkylsilyl andaryldialkylsilyl.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² is hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tort-butyl,cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl,2-pyridyl, 3-pyridyl or 4-pyridyl, R³ is hydrogen and R⁴ is selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl,substituted C₇₋₉ phenylalkyl, trialkylsilyl and aryldialkylsilyl.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² is hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclohexyl or phenyl,R³ is hydrogen and R⁴ is selected from the group consisting of hydrogen,C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, substitutedphenyl, C₇₋₉ phenylalkyl, substituted C₇₋₉ phenylalkyl, trialkylsilyland aryldialkylsilyl.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² is methyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl, or cyclohexyloxycarbonyl, R³ ismethyl and R⁴ is selected from the group consisting of hydrogen, C₁₋₆alkyl, substituted C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, substitutedphenyl, C₇₋₉ phenylalkyl, substituted C₇₋₉ phenyl alkyl, trialkylsilyland aryldialkylsilyl.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² and R³ are independently selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl, substituted C₁₋₄alkyl, C₁₋₄ alkoxycarbonyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxycarbonyl,phenyl, substituted phenyl, C₇₋₉ phenylalkyl and pyridyl and R⁴ ishydrogen, methyl, ethyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl,diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl,triisopropylsilyl, tert-butyldimethylsilyl or phenyldimethylsilyl.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² is hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl,2-pyridyl, 3-pyridyl or 4-pyridyl, R³ is hydrogen and R⁴ is hydrogen,methyl, ethyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl,diphenylmethyl, triphenylmethyl, trimethylsilyl, triethylsilyl,triisopropylsilyl, tert-butyldimethylsilyl or phenyldimethylsilyl.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² is hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclohexyl or phenyl,R³ is hydrogen and R⁴ is hydrogen, methyl, ethyl, tert-butyl, allyl,benzyl, 4-methoxybenzyl, diphenylmethyl, triphenylmethyl,trimethylsilyl, triethylsilyl, triisopropylsilyl,tert-butyldimethylsilyl or phenyldimethylsilyl.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² is methyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl, or cyclohexyloxycarbonyl, R³ ismethyl and R⁴ is hydrogen, methyl, ethyl, tert-butyl, allyl, benzyl,4-methoxybenzyl, diphenylmethyl, triphenylmethyl, trimethylsilyl,triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl orphenyldimethylsilyl.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² and R³ are independently selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl, substituted C₁₋₄alkyl, C₁₋₄ alkoxycarbonyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxycarbonyl,phenyl, substituted phenyl, C₇₋₉ phenylalkyl and pyridyl and R⁴ ishydrogen, allyl, benzyl or trimethylsilyl.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² is hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl,2-pyridyl, 3-pyridyl or 4-pyridyl, R³ is hydrogen and R⁴ is hydrogen,allyl, benzyl or trimethylsilyl.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² is hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclohexyl or phenyl,R³ is hydrogen and R⁴ is hydrogen, allyl, benzyl or trimethylsilyl.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² is methyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl, or cyclohexyloxycarbonyl, R³ ismethyl and R⁴ is hydrogen, allyl, benzyl or trimethylsilyl.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² and R³ are independently selectedfrom the group consisting of hydrogen, C₁₋₄ alkyl, substituted C₁₋₄alkyl, C₁₋₄ alkoxycarbonyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxycarbonyl,phenyl, substituted phenyl, C₇₋₉ phenylalkyl and pyridyl and R⁴ ishydrogen.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² is hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl,2-pyridyl, 3-pyridyl or 4-pyridyl, R³ is hydrogen and R⁴ is hydrogen.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² is hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, cyclohexyl or phenyl,R³ is hydrogen and R⁴ is hydrogen.

In still other embodiments, of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² is methyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl, or cyclohexyloxycarbonyl, R³ ismethyl and R⁴ is hydrogen.

In still other embodiments of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² is hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenyl or cyclohexyl,R³ is hydrogen and R⁴ is hydrogen, allyl, benzyl or trimethylsilyl. Inother embodiments of a compound of Formulae (II), (VII) or (VIII), X ischloro, bromo or iodo, R² is hydrogen, methyl, n-propyl, or isopropyl,R³ is hydrogen and R⁴ is hydrogen, allyl, benzyl or trimethylsilyl. Instill other embodiments of a compound of Formulae (II), (VII) or (VIII),X is chloro, R² is hydrogen, methyl, n-propyl, or isopropyl, R³ ishydrogen and R⁴ is hydrogen, allyl, benzyl or trimethylsilyl.

In still other embodiments of a compound of Formulae (II), (VII) or(VIII), X is chloro, bromo or iodo, R² is methyl, methoxycarbonyl,ethoxycarbonyl, isopropoxycarbonyl or cyclohexyloxycarbonyl R³ is methyland R⁴ is hydrogen, allyl, benzyl or trimethylsilyl.

Compounds of Formulae (II), (VII) and (VIII) are useful intermediates inthe synthesis of compounds of Formulae (I), (VI) and (VII), as describedin detail in Section 4.3 below.

4.3 Synthesis

The compounds disclosed herein may be obtained via the synthetic methodsillustrated in Schemes 1-10. Those of ordinary skill in the art willappreciate that a preferred synthetic route to the disclosed compoundsconsists of attaching promoieties to baclofen or baclofen analogs.Numerous methods have been described in the art for the synthesis ofbaclofen and baclofen analogs (e.g., Keberle et al., U.S. Pat. No.3,471,548; Keberle et al., U.S. Pat. No. 3,634,428; Krogsgaard-Larsen,Med. Res. Rev. 1988, 8, 27-56; Berthelot et al., J. Med. Chem. 1987, 30,743-746; Berthelot et al., J. Med. Chem. 1991, 34, 2557-2560; Debaert etal., European Patent No. EP 0463969 B1). Methods for preparation ofR-baclofen have also been described in the art (e.g., Witczuk et al.,Pol. J. Pharmacol. Pharm. 1980, 32, 187-196; Chenevert et al.,Tetrahedron Lett. 1991, 32, 4249-4250; Herdeis et al., TetrahedronAsymmetry 1992, 3, 1213-1221; Hubmann et al., German Patent ApplicationNo. DE 4224342 A1; Yoshifuji et al., Chem Pharm. Bull. 1995, 43,1302-1306; Wildervanck et al., U.S. Pat. No. 6,051,734; Thakur et al.,Tetrahedron Asymmetry 2003, 14, 581-586). Other prodrug (or related)derivatives of baclofen have been described in the art (e.g., Kaplan etal., U.S. Pat. No. 4,094,992; Mazaki et al., Jpn. Kokai Tokkyo Koho JP01319466 A2; Castagnoli et al., International Publication No.WO98/22110; Guillon et al. Pharm. Pharmacol. Commun. 1999, 5, 243-247;Leisen et al., Pharm. Res. 2003, 20, 772-778; Mills, U.S. Pat. No.5,773,592; Mills, U.S. Patent Appl. Publ. 2003/0228644). Generalsynthetic methods useful in the synthesis of the compounds describedherein are available in the art (e.g., Green et al., “Protective Groupsin Organic Chemistry”, (Wiley, 2^(nd) ed. 1991); Harrison et al.,“Compendium of Synthetic Organic Methods”, Vols. 1-8 (John Wiley andSons, 1971-1996; Larock “Comprehensive Organic Transformations,” VCHPublishers, 1989; and Paquette, “Encyclopedia of Reagents for OrganicSynthesis,” John Wiley & Sons, 1995).

Accordingly, starting materials useful for preparing compounds andintermediates thereof, and/or practicing methods described herein arecommercially available or can be prepared by well-known syntheticmethods. Other methods for synthesis of the prodrugs described hereinare either described in the art or will be readily apparent to theskilled artisan in view of the references provided above and may be usedto synthesize the compounds described herein. Accordingly, the methodspresented in the Schemes herein are illustrative rather thancomprehensive.

Intermediate (XI) useful in the preparation of 1-haloalkyl carbamates ofFormula (II) may be generated according to reactions detailed in Scheme1.

The amino group of (IV) is protected under standard conditions with aprotecting group (Pg) to afford compound (IX). The carboxylic acidmoiety in (IX) is esterified to yield compound (X), either viaalkylation with R⁴—Y, where Y is halide, —OSO₂R′ (R′ is alkyl,substituted alkyl, aryl or substituted aryl) or any other suitableleaving group or via condensation with alcohol R⁴—OH under standardacylation conditions (e.g., in the presence of a coupling agent such asa carbodiimide, via an acyl halide, acid anhydride or other activatedester intermediate). Removal of the protecting group from (X) understandard deprotection conditions affords compound (XI). Preferably, theprotecting group Pg is removable under acidic conditions and compound(XI) is isolated as a salt, which is stabilized against lactam formationrelative to the corresponding free base. tert-Butoxycarbonyl (i.e., Boc)is one preferred protecting group, and may be removed with HCl to afford(XI) as a hydrochloride salt.

In some embodiments, the hydrochloride salt of (XI) is prepared directlyfrom (IV) by treatment with an excess of thionyl chloride or hydrogenchloride gas and alcohol R⁴—OH (Scheme 2). Typical ratios of (IV) tothionyl chloride from between about 1:1 and about 1:20, and ratios of(IV) to alcohol from between about 1:1 and about 1:20 may be used. Thereaction may be performed at temperatures between about −20° C. andabout 25° C. The alcohol may be used as a solvent for the reaction underconditions where R⁴—OH is a liquid. Alternatively, the reaction may beperformed in a suitable solvent, such as dichloromethane,dichloroethane, chloroform, toluene, dimethylformamide,dimethylacetamide, N-methylpyrrolidinone, pyridine or combinationsthereof. Preferred alcohols R⁴—OH for this reaction include arylalkyl,substituted arylalkyl and allylic alcohols. Allyl alcohol and benzylalcohol are particularly preferred.

In some embodiments, a compound of Formula (II) is prepared by acylationof (XI) with compound (XII) (see Scheme 3), where X is halide and Z is aleaving group (e.g., halide, p-nitrophenolate, imidazolyl, etc.). Inother embodiments, X is Cl, Br or I and Z is Cl. In yet otherembodiments, X and Z are both Cl. The acylation reaction may beperformed in the presence of a inorganic base or an organic base (e.g.,tertiary amine bases, such as triethylamine, tributylamine,diisopropylethylamine, dimethylisopropylamine, N-methylmorpholine,N-methylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyridine,2,6-dimethylpyridine, 4-dimethylaminopyridine,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene or1,5-diazabicyclo[4.3.0]undec-7-ene or combinations thereof) orcombinations thereof. Suitable solvents for acylation include, but arenot limited to, dichloromethane, dichloroethane, chloroform, toluene,dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, pyridine, ethyl acetate, isopropyl acetate, acetonitrile,acetone, 2-butanone, methyl tert-butyl ether or combinations thereof.Alternatively, biphasic solvent mixtures comprising water and includingone or more of dichloromethane, dichloroethane, chloroform, toluene,ethyl acetate, isopropyl acetate or methyl tert-butyl ether, may beutilized. Typical temperatures for performing this reaction are betweenabout −20° C. and about 50° C., more preferably between about −20° C.and about 25° C.

In other embodiments, a compound of Formula (II), where R⁴ istrialkylsilyl or aryldialkylsilyl, may be prepared directly fromcompound (IV) by silylation (e.g., using a silyl halide or silylamidereagent) followed by acylation of the resulting intermediate withcompound (XII) (see Scheme 4). Suitable solvents for performing thisreaction include, but are not limited to, dichloromethane,dichloroethane, chloroform, toluene, pyridine, acetonitrile orcombinations thereof. Suitable bases for performing this reactioninclude but are not limited to, triethylamine, tributylamine,diisopropylethylamine, dimethylisopropylamine, N-methylmorpholine,N-methylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyridine,2,6-dimethylpyridine, 4-dimethylaminopyridine,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]undec-7-ene or combinations thereof. Typicaltemperatures for performing this reaction are between about −78° C. andabout 50° C., more preferably between about −20° C. and about 25° C.

In still other embodiments, 1-acyloxylalkyl carbamates of Formula (I)are prepared from compounds of Formula (II) by treatment with carboxylicacids of Formula (III) in the presence of an organic or inorganic base,or other metal salt, as illustrated in Scheme 5.

Those of skill in the art will appreciate that the followingembodiments, infra, refer to compounds of Formulae (I), (II) and (III).In some embodiments, the ratio of the compound of Formula (II) to thecompound of Formula (III) is between about 1:1 and 1:20. In otherembodiments, the ratio of the compound of Formula (II) to the compoundof Formula (III) is between about 1:1 and 1:5. In still otherembodiments, the ratio of the compound of Formula (II) to the compoundof Formula (III) is about 1:1.

In some embodiments, the compounds of Formulae (II) and (III) and themetal salt are contacted with a solvent. In other embodiments, the ratioof the compound of Formula (II) to the compound of Formula (III) isbetween about 1:1 and 1:20. In still other embodiments, the ratio of thecompound of Formula (II) to the compound of Formula (III) is betweenabout 1:1 and 1:5. In still other embodiments, the ratio of the compoundof Formula (II) to the compound of Formula (III) is about 1:1. In someembodiments, the solvent is dichloromethane, dichloroethane, chloroform,toluene, dimethylformamide, dimethylacetamide, N-methylpyrrolidinone,dimethyl sulfoxide, pyridine, ethyl acetate, acetonitrile, acetone,2-butanone, methyl tert-butyl ether, methanol, ethanol, isopropanol,tert-butanol, water, hexamethylphosphoramide or combinations thereof. Inother embodiments, the metal is Ag, Hg, Na, K, Li, Cs, Ca, Mg or Zn.

In some embodiments, the compounds of Formulae (II) and (III) and theorganic base are contacted with a solvent. In other embodiments, theratio of the compound of Formula (II) to the compound of Formula (III)is between about 1:1 and 1:20. In still other embodiments, the ratio ofthe compound of Formula (II) to the compound of Formula (III) is betweenabout 1:15 and 1:20. In still other embodiments, the ratio of thecompound of Formula (II) to the compound of Formula (III) is about 1:10.In still other embodiments, the ratio of the compound of Formula (II) tothe compound of Formula (III) is between about 1:1 and 1:5. In stillother embodiments, the ratio of the compound of Formula (II) to thecompound of Formula (III) is about 1:1. In some embodiments, the solventis dichloromethane, dichloroethane, chloroform, toluene,dimethylformamide, dimethylacetamide, N-methylpyrrolidinone, dimethylsulfoxide, pyridine, ethyl acetate, acetonitrile, acetone, 2-butanone,methyl tert-butyl ether, methanol, ethanol, isopropanol, tert-butanol,water, hexamethylphosphoramide or combinations thereof. In otherembodiments, the organic base is triethylamine, tributylamine,diisopropylethylamine, dimethylisopropylamine, N-methylmorpholine,N-methylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyridine,2,6-dimethylpyri dine, 4-dimethylaminopyridine,1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]undec-7-ene,1,5-diazabicyclo[4.3.0]undec-7-ene or combinations thereof.

In some embodiments, the compound of Formula (III) is a liquid under theconditions of said contacting, the compound of Formula (III) furtherserving as a solvent for the reaction with the compound of Formula (II).In other embodiments, the compound of Formula (III) is acetic acid,methoxyacetic acid, ethoxyacetic acid, propionic acid, butyric acid,isobutyric acid, pivalic acid, valeric acid, isovaleric acid,2-methylbutyric acid, cyclobutanecarboxylic acid, cyclopentanecarboxylicacid or cyclohexanecarboxylic acid.

In some embodiments, the compound of Formula (II), the compound ofFormula (III) and the metal salt are contacted at a temperature betweenabout −25° C. and about 120° C. In other embodiments, the temperature isbetween about 0° C. and about 25° C.

In still some other embodiments, the compound of Formula (II), thecompound of Formula (III) and the organic base are contacted at atemperature between about −25° C. and about 120° C. In otherembodiments, the temperature is between about 0° C. and about 25° C.

In some embodiments, the compound of Formula (II), the compound ofFormula (III) and the organic base are contacted with a catalytic amountof an iodide salt. In still other embodiments, the iodide salt is sodiumiodide, potassium iodide, tetramethylammonium iodide, tetraethylammoniumiodide or tetrabutylammonium iodide.

In some embodiments, R⁴ is a carboxylic acid protecting group that canbe removed under mild conditions to provide a compound of Formula (I)where R⁴ is hydrogen. Carboxylic acid protecting groups removable viamild acidic hydrolysis, fluoride ion-promoted hydrolysis, catalytichydrogenolysis, transfer hydrogenolysis, or other transitionmetal-mediated deprotection reactions are preferred. In someembodiments, R⁴ is trimethylsilyl, allyl or benzyl.

In still other embodiments compounds of Formula (I) are prepared asillustrated in Scheme 6.

Chloroformate (XIII) is treated with an aromatic leaving group such asp-nitrophenol in the presence of base to provide p-nitrophenylcarbonate(XIV). Halide interchange provides iodide (XV), which is reacted with ametal or tetraalkylammonium salt of a carboxylic acid to afford compound(XVI). Treatment of (XVI) with baclofen analog derivative (XI),optionally, in the presence of trimethylsilyl chloride, affords acompound of Formula (I). Methods for making related acyloxyalkylcarbamate compounds have been described in the art (Alexander, U.S. Pat.No. 4,760,057; Alexander, U.S. Pat. No. 4,916,230; Alexander, U.S. Pat.No. 5,466,811; Alexander, U.S. Pat. No. 5,684,018).

Another method for synthesis of compounds of Formula (I) proceeds viacarbonylation of baclofen analog derivative (XI) to an intermediatecarbamic acid species, which is captured by an in situ alkylationreaction in an adaptation of methods disclosed in the art (Butcher,Synlett 1994, 825-6; Ferres et al., U.S. Pat. No. 4,036,829). Carbondioxide gas is bubbled into a solution containing (XI) and a base (e.g.,Cs₂CO₃, Ag₂CO₃ or AgO) in a solvent such as DMF or NMP. The activatedhalide is added, optionally, in the presence of iodide ion as acatalyst, and the carbonylation continued until the reaction iscompleted. This method is illustrated in Scheme 7 for the preparation ofcompounds of Formula (I) from halide (XVII).

Yet another method for synthesis of compounds of Formula (I) relies uponoxidation of ketocarbamate derivatives of baclofen and baclofen analogs(e.g., Gallop et al., U.S. Patent Appl. Publ. 2003/0171303; and Bhat etal., U.S. Pat. No. 8,017,776 entitled “Methods for Synthesis ofAcyloxyalkyl Compounds”). As illustrated in Scheme 8, oxidation ofketocarbamate (XVIII) affords a compound of Formula (I). Methods forsynthesis of compounds of Formula (XVIII) are disclosed in the pendingapplications, supra. Typical oxidants include those, which have beensuccessfully used in Baeyer-Villager oxidations of ketones to esters orlactones (Strukul, Angnew. Chem. Int. Ed. 1998, 37, 1198; Renz et al.,Eur. J. Org. Chem. 1999, 737; Beller et al., in “Transition Metals inOrganic Synthesis” Chapter 2, Wiley VCH; Stewart, Current OrganicChemistry, 1998, 2, 195; Kayser et al., Synlett 1999, 1, 153). The useof anhydrous oxidants may be beneficial since prodrugs (I) may belabile. Thus, performing the oxidation under anhydrous reactionconditions may avoid hydrolysis of the reactive products.

Preferably, the oxidation is performed in the liquid phase, morepreferably, in the presence of a solvent. Choosing a solvent foroxidation of a compound of Formula (XVIII) is well within the ambit ofone of skill in the art. Generally, a useful solvent will dissolve, atleast partially, both the oxidant and the compound of Formula (XVIII)and will be inert to the reaction conditions. Preferred solvents areanhydrous and include, but are not limited to, dichloromethane,dichloroethane, chloroform, ethyl acetate, isopropyl acetate, toluene,chlorobenzene, xylene, acetonitrile, diethyl ether, methyl tert-butylether, acetic acid, cyclohexane and hexanes. Mixtures of the abovesolvents may also be used in the oxidation of a compound of Formula(XVIII) to a compound of Formula (I).

In some embodiments, the anhydrous oxidant is an anhydrous peroxyacidgenerated in situ by reaction of the urea-hydrogen peroxide complex (4)(“UHP”) with a carboxylic acid anhydride. In other embodiments, theanhydrous oxidant is an anhydrous peroxysulfonic acid generated in situby reaction of the urea-hydrogen peroxide complex (4) with a sulfonicacid anhydride. The UHP complex serves as a source of anhydrous hydrogenperoxide and has been used in a variety of oxidative transformations inanhydrous organic solvents (Cooper et al., Synlett. 1990, 533-535;Balicki et al., Synth. Commun. 1993, 23, 3149; Astudillo et al.,Heterocycles 1993, 36, 1075-1080; Varma et al., Organic Lett. 1999, 1,189-191). However, other suitable sources of anhydrous hydrogen peroxidemay also be used in the reaction instead of the UHP-complex (e.g., the1,4-diazabicyclo[2.2.2]octane-hydrogen peroxide complex).

A useful oxidant is anhydrous peroxytrifluoroacetic acid, generated insitu by reacting the UHP-complex with trifluoroacetic anhydride (Cooperet al., Synlett. 1990, 533-535; Benjamin, et al., J. Am. Chem. Soc.2002, 124, 827-833). Anhydrous peroxycarboxylic acids (XX) may generallybe prepared by treating carboxylic acid anhydrides with anhydroushydrogen peroxide, more preferably, with the UHP-complex (4). Similarly,anhydrous peroxysulfonic acids (XXII) may be prepared by reactingsulfonic acid anhydrides (XXI) with anhydrous hydrogen peroxide,preferably, with the UHP-complex (4). The preparation of anhydrousperoxycarboxylic acids (XX) and the peroxysulfonic acids (XXII) isillustrated in Scheme 9.

The UHP-complex (4) and a carboxylic acid anhydride (XIX) or a sulfonicacid anhydride (XXI) are reacted in dichloromethane or other suitablesolvent at temperatures ranging from about −25° C. to about 100° C. togenerate the anhydrous peroxyacids. The peroxyacids may be generatedfirst and subsequently reacted with the ketocarbamate (XVIII). In someembodiments, a carboxylic acid anhydride is added to a stirredsuspension or solution containing the UHP-complex and (XVIII) togenerate the peroxycarboxylic acid, which reacts in situ with (XVIII) togive compound (I). In other embodiments, the molar ratio of UHP-complexand the acid anhydride is about 6:1. In still other embodiments, themolar ratio of UHP-complex and acid anhydride (XIX) is between about 5:1and about 1:1. In yet other embodiments, the molar ratio of UHP-complexand acid anhydride (XIX) is between about 2:1 and about 1:1.

In some embodiments, the molar ratio of the peroxyacid oxidant to thecompound of Formula (XVIII) is between about 8:1 and about 1:1. In otherembodiments, the molar ratio of the peroxyacid oxidant to the compoundof Formula (XVIII) is between about 4:1 and about 1:1. In yet otherembodiments, the molar ratio of the peroxyacid oxidant to the compoundof Formula (XVIII) is between about 2:1 and about 1:1. Preferably, whenthe oxidant is peroxytrifluoroacetic acid or another substitutedperoxyacetic acid, the molar ratio of the peroxyacid oxidant to thecompound of Formula (XVIII) is about 2:1.

Further, the use of additives in the oxidation of a compound of Formula(XVIII) to a compound of Formula (I) is also contemplated. While notwishing to be bound by theory, additives may either catalyze thereaction or stabilize the final product or both. In some embodiments, aLewis acid or a protic acid or any combination of Lewis acid or proticacid may be used in the oxidation of a compound of Formula (XVIII)(preferably, in the presence of a solvent). Lewis acids include, but arenot limited to, BF₃, SeO₂, MeReO₃, MnO₂, SnC1₄, Sc(OTf)₃, Ti(O-iPr)₄,Al₂O₃ and Fe₂O₃. Protic acids include, but are not limited to,trifluoroacetic acid, acetic acid, p-toluenesulfonic acid,methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acidand sulfuric acid. While not wishing to be bound by theory, the Lewisacid and/or protic acid may catalyze oxidation by increasing theelectrophilicity of the carbonyl group in Formula (XVIII).

In other embodiments, the oxidation may be conducted in the presence ofan anhydrous base. While not wishing to be bound by theory, the base maystabilize acid sensitive products by reacting with acidic by-productsformed during oxidation.

Generally, the temperature of the reaction may be readily optimized bymethods known to those of ordinary skill in the art. Preferably, theoxidation of a compound of Formula (XVIII) is carried out at atemperature between about −25° C. and about 100° C. (more preferably,between about 0° C. and about 25° C.).

An advantageous feature of this method of synthesis of compounds ofFormula (I) is that oxidation of ketocarbamate derivatives (XVIII)proceeds stereospecifically, with retention of configuration at thecarbon atom initially adjacent to the carbonyl group in ketone (XVIII).This may be exploited in a stereoselective synthesis of prodrugderivatives. For example, the chiral R-baclofen prodrug 4-{[(1S)-isobutanoyloxyethoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoicacid (34) may be synthesized as a single diastereomer by stereoselectiveoxidation of4-{[(1S)-isobutanoylethoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoicacid (35) as described in Example 30 of Section 5 below. Acyloxyalkylprodrugs of other baclofen analogs may be amenable to synthesis from theappropriate ketocarbamate derivatives via Baeyer-Villiger typeoxidation, provided that they do not contain chemical functionalitysusceptible to decomposition or other transformation under conditions ofthe reaction.

Another method for synthesis of compounds of Formula (I), illustrated inScheme 10, relies upon reaction of compounds of Formulae (IV) or (XI)with a 1-(acyloxy)-alkyl N-hydroxysuccinimidyl carbonate compound ofFormula (XXIII), as described in the co-pending application Gallop etal., U.S. Provisional Patent Application Ser. No. 60/606,637 entitled“Methods for Synthesis of Acyloxyalkyl Carbamate Prodrugs,” filed Aug.13, 2004).

wherein R⁹ and R¹⁰ are independently hydrogen, acylamino, acyloxy,alkoxycarbonylamino, alkoxycarbonyloxy, alkyl, substituted alkyl,alkoxy, substituted alkoxy, aryl, substituted aryl, arylalkyl,carbamoyloxy, dialkylamino, heteroaryl, hydroxy, sulfonamido, oroptionally, R⁹ and R¹⁰ together with the atoms to which they areattached form a substituted cycloalkyl, substituted cycloheteroalkyl orsubstituted aryl ring and R¹ to R⁵ are as described in Section 4.2.

In some embodiments of the method described in Scheme 10 forsynthesizing a compound of Formula (I), R² and R³ in the compound ofFormula (XXIII) are different, such that the carbon atom to which thesesubstituents are attached is a stereogenic center.

In some embodiments of the method described in Scheme 10 forsynthesizing a compound of Formula (I), R⁹ and R¹⁰ in the compound ofFormula (XXIII) are each benzoyloxy, the stereochemistry at the carbonto which R⁹ is attached is of the R-configuration, and thestereochemistry at the carbon to which R¹⁰ is attached is of theR-configuration. In other embodiments of the method described in Scheme10 for synthesizing a compound of Formula (I), R⁹ and R¹⁰ in thecompound of Formula (XXIII) are each benzoyloxy, the stereochemistry atthe carbon to which R⁹ is attached is of the S-configuration and thestereochemistry at the carbon to which R¹⁰ is attached is of theS-configuration.

In some embodiments of the methods for synthesizing a compound ofFormula (I), R² and R³ in the compound of Formula (I) are different andthe compound of Formula (I) is substantially one diastereomer. In someembodiments of the method described in Scheme 10 for synthesizing acompound of Formula (I), R¹ is isopropyl, R² is isopropyl, R³ ishydrogen, the stereochemistry at the carbon to which R² and R³ areattached is of the S-configuration and the compound of Formula (I) issubstantially one diastereomer. In still other embodiments of the methodof Scheme 10 for synthesizing a compound of Formula (I), R¹ isisopropyl, R² is isopropyl, R³ is hydrogen, the stereochemistry at thecarbon to which R² and R³ are attached is of the R-configuration, andthe compound of Formula (I) is substantially one diastereomer.

In some embodiments of the method of Scheme 10 for synthesizing acompound of Formula (I), R¹ is C₁₋₆ alkyl, R² is hydrogen or C₁₋₄ alkyl,R³ is hydrogen, R⁴ is hydrogen, R⁵ is 4-chlorophenyl, R⁹ and R¹⁰ areeach benzoyloxy, and the stereochemistry at the carbon to which R⁵ isattached is of the R-configuration. In still other embodiments of themethod of Scheme 10 for synthesizing a compound of Formula (I), R¹ isisopropyl, R² is isopropyl, R³ is hydrogen, R⁴ is hydrogen, R⁵ is4-chlorophenyl, R⁹ and R¹⁰ are each benzoyloxy, and the stereochemistryat the carbon to which R⁵ is attached is of the R-configuration.

In still other embodiments of the method of Scheme 10 for synthesizing acompound of Formula (I), R¹ is isopropyl, R² is isopropyl, R³ ishydrogen, R⁴ is hydrogen, R⁵ is 4-chlorophenyl, R⁹ and R¹⁰ are eachbenzoyloxy, the stereochemistry at the carbon to which R² and R³ areattached is of the S-configuration, the stereochemistry at the carbon towhich R⁵ is attached is of the R-configuration, the stereochemistry atthe carbon to which R⁹ is attached is of the R-configuration, and thestereochemistry at the carbon to which R¹⁰ is attached is of theR-configuration. In still other embodiments of the method of Scheme 10for synthesizing a compound of Formula (I), R¹ is isopropyl, R² isisopropyl, R³ is hydrogen, R⁴ is hydrogen, R⁵ is 4-chlorophenyl, R⁹ andR¹⁰ are each benzoyloxy, the stereochemistry at the carbon to which R²and R³ are attached is of the R-configuration, the stereochemistry atthe carbon to which R⁵ is attached is of the R-configuration, thestereochemistry at the carbon to which R⁹ is attached is of theS-configuration and the stereochemistry at the carbon to which R¹⁰ isattached is of the S-configuration.

In some embodiments, the method of Scheme 10 is carried out in asolvent. Useful solvent include, but are not limited to, acetone,acetonitrile, dichloromethane, dichloroethane, chloroform, toluene,tetrahydrofuran, dioxane, dimethylformamide, dimethylacetamide,N-methylpyrrolidinone, dimethyl sulfoxide, pyridine, ethyl acetate,methyl tert-butyl ether, methanol, ethanol, isopropanol, tert-butanol,water or combinations thereof. Preferably, the solvent is acetone,acetonitrile, dichloromethane, toluene, tetrahydrofuran, pyridine,methyl tert-butyl ether, methanol, ethanol, isopropanol, water, orcombinations thereof. In some embodiments, the solvent is a mixture ofacetonitrile and water. In other embodiments, the solvent is a mixtureof acetonitrile and water, with a volume ratio of acetonitrile to waterfrom about 1:5 to about 5:1. In still other embodiments, the solvent isa mixture of methyl tert-butyl ether and water. In still otherembodiments, the solvent is a mixture of methyl tert-butyl ether andwater, with a volume ratio of methyl tert-butyl ether to water fromabout 20:1 to about 2:1. In still other embodiments, the solvent is amixture of methyl tert-butyl ether and water, wherein the methyltert-butyl ether contains from about 10% to about 50% acetone by volume.In still other embodiments, the solvent is dichloromethane, water or acombination thereof. In still other embodiments, the solvent is abiphasic mixture of dichloromethane and water. In still otherembodiments, the solvent is a biphasic mixture of dichloromethane andwater containing from about 0.001 equivalents to about 0.1 equivalentsof a phase transfer catalyst. Preferably, the phase transfer catalyst isa tetraalkylammonium salt, more preferably, the phase transfer catalystis a tetrabutylammonium salt.

The method of Scheme 10 is preferably carried out a temperature betweenabout −20° C. and about 40° C. In some embodiments, the temperature isbetween about −20° C. and about 25° C. In other embodiments, thetemperature is between about 0° C. and about 25° C. In still otherembodiments, the temperature is between about 25° C. and about 40° C.

In some embodiments of the method of Scheme 10, the reaction isperformed in the absence of a base.

In other embodiments of the method of Scheme 10, the reaction isperformed in the presence of an inorganic base. In some embodiments, thereaction is performed in the presence of an alkali metal bicarbonate oralkali metal carbonate salt. In other embodiments, the reaction isperformed in the presence of sodium bicarbonate.

In still other embodiments of the method of Scheme 10, the reaction isperformed in the presence of an organic base. Preferably, the reactionis performed in the presence of triethylamine, tributylamine,diisopropylethylamine, dimethylisopropylamine, N-methylmorpholine,N-methylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyridine,2,6-dimethylpyridine, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, 1, 8-diazabicyclo[5.4.0]undec-7-ene or 1,5-diazabicyclo[4.3.0]undec-7-ene, more preferably, the reaction isperformed in the presence of triethylamine, diisopropylethylamine,N-methylmorpholine, or pyridine.

4.4 Pharmaceutical Compositions

Pharmaceutical compositions comprising a therapeutically effectiveamount of one or more baclofen or baclofen analog prodrug compounds ofFormulae (I), (V) or (VI), preferably in purified form, together with asuitable amount of a pharmaceutically acceptable vehicle, so as toprovide a form for proper administration to a patient are providedherein. Suitable pharmaceutical vehicles include excipients such asstarch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk,silica gel, sodium stearate, glycerol monostearate, talc, sodiumchloride, dried skim milk, glycerol, propylene, glycol, water, ethanoland the like. The present compositions, if desired, can also containminor amounts of wetting or emulsifying agents, or pH buffering agents.In addition, auxiliary, stabilizing, thickening, lubricating andcoloring agents may be used.

Pharmaceutical compositions may be manufactured by means of conventionalmixing, dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxiliaries, which facilitate processing of compounds disclosed hereininto preparations which can be used pharmaceutically. Proper formulationis dependent upon the route of administration chosen.

The present pharmaceutical compositions can take the form of solutions,suspensions, emulsion, tablets, pills, pellets, capsules, capsulescontaining liquids, powders, sustained-release formulations,suppositories, emulsions, aerosols, sprays, suspensions, or any otherform suitable for use. In some embodiments, the pharmaceuticallyacceptable vehicle is a capsule (see e.g., Grosswald et al., U.S. Pat.No. 5,698,155). Other examples of suitable pharmaceutical vehicles havebeen described in the art (see Remington's Pharmaceutical Sciences,Philadelphia College of Pharmacy and Science, 19th Edition, 1995). Insome embodiments, compositions are formulated for oral delivery,particularly for oral sustained release administration.

Pharmaceutical compositions for oral delivery may be in the form oftablets, lozenges, aqueous or oily suspensions, granules, powders,emulsions, capsules, syrups, or elixirs, for example. Orallyadministered compositions may contain one or more optional agents, forexample, sweetening agents such as fructose, aspartame or saccharin,flavoring agents such as peppermint, oil of wintergreen, or cherrycoloring agents and preserving agents, to provide a pharmaceuticallypalatable preparation. Moreover, when in tablet or pill form, thecompositions may be coated to delay disintegration and absorption in thegastrointestinal tract, thereby providing a sustained action over anextended period of time. Oral compositions can include standard vehiclessuch as mannitol, lactose, starch, magnesium stearate, sodiumsaccharine, cellulose, magnesium carbonate, etc. Such vehicles arepreferably of pharmaceutical grade.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,saline, alkyleneglycols (e.g., propylene glycol), polyalkylene glycols(e.g., polyethylene glycol) oils, alcohols, slightly acidic buffersbetween pH 4 and pH 6 (e.g., acetate, citrate, ascorbate at betweenabout 5 mM to about 50 mM), etc. Additionally, flavoring agents,preservatives, coloring agents, bile salts, acylcarnitines and the likemay be added.

When a compound of Formulae (I), (V) or (VI) is acidic, it may beincluded in any of the above-described formulations as the free acid, apharmaceutically acceptable salt, a solvate or hydrate. Pharmaceuticallyacceptable salts substantially retain the activity of the free acid, maybe prepared by reaction with bases, and tend to be more soluble inaqueous and other protic solvents than the corresponding free acid form.In some embodiments, sodium salts of a compound of Formulae (I), (V) or(VI) are used in the above described formulations.

4.5 Sustained Release Oral Dosage Forms

The disclosed compounds can be used with a number of different dosageforms, which may be adapted to provide sustained release of a compoundof Formulae (I), (V) or (VI) upon oral administration.

In some embodiments, the dosage form comprises beads that on dissolutionor diffusion release a compound disclosed herein over an extended periodof hours, preferably, over a period of at least 6 hours, morepreferably, over a period of at least 8 hours and most preferably, overa period of at least 12 hours. The beads may have a central compositionor core comprising a compound disclosed herein and pharmaceuticallyacceptable vehicles, including an optional lubricant, antioxidant andbuffer. The beads may be medical preparations with a diameter of about0.05 mm to about 2 mm. Individual beads may comprise doses of a compounddisclosed herein, for example, doses of up to about 40 mg of compound.The beads, in some embodiments, are formed of non-cross-linked materialsto enhance their discharge from the gastrointestinal tract. The beadsmay be coated with a release rate-controlling polymer that gives a timedrelease profile.

The time-release beads may be manufactured into a tablet fortherapeutically effective administration. The beads can be made intomatrix tablets by the direct compression of a plurality of beads coatedwith, for example, an acrylic resin and blended with excipients such ashydroxypropylmethyl cellulose. The manufacture of beads has beendisclosed in the art (Lu, Int. J. Pharm., 1994, 112, 117-124;Pharmaceutical Sciences by Remington, 14^(th) ed, pp 1626-1628 (1970);Fincher, J. Pharm. Sci. 1968, 57, 1825-1835; and U.S. Pat. No.4,083,949) as has the manufacture of tablets (Pharmaceutical Sciences,by Remington, 17^(th) Ed, Ch. 90, pp 1603-1625 (1985).

One type of sustained release oral dosage formulation that may be usedwith the disclosed compounds comprises an inert core, such as a sugarsphere, coated with an inner drug-containing layer and an outer membranelayer controlling drug release from the inner layer. A “sealcoat” may beprovided between the inert core and the layer containing the activeingredient. When the core is of a water-soluble or water-swellable inertmaterial, the sealcoat is preferably in the form of a relatively thicklayer of a water-insoluble polymer. Such a controlled release bead maythus comprise: (i) a core unit of a substantially water-soluble orwater-swellable inert material; (ii) a first layer on the core unit of asubstantially water-insoluble polymer; (iii) a second layer covering thefirst layer and containing an active ingredient; and (iv) a third layeron the second layer of polymer effective for controlled release of theactive ingredient, wherein the first layer is adapted to control waterpenetration into the core.

Usually, the first layer (ii) above constitutes more than about 2% (w/w)of the final bead composition, preferably, more than about 3% (w/w),e.g., from about 3% to about 80% (w/w). The amount of the second layer(ii) above usually constitutes from about 0.05% to about 60% (w/w),preferably from about 0.1% to about 30% (w/w) of the final beadcomposition. The amount of the third layer (iv) above usuallyconstitutes from about 1% to about 50% (w/w), preferably, from about 2%to about 25% (w/w) of the final bead composition. The core unittypically has a size in the range of from about 0.05 to about 2 mm. Thecontrolled release beads may be provided in a multiple unit formulation,such as a capsule or a tablet.

The cores are preferably of a water-soluble or swellable material andmay be any such material that is conventionally used as cores or anyother pharmaceutically acceptable water-soluble or water-swellablematerial made into beads or pellets. The cores may be spheres ofmaterials such as sucrose/starch (Sugar Spheres NF), sucrose crystals,or extruded and dried spheres typically comprised of excipients such asmicrocrystalline cellulose and lactose. The substantiallywater-insoluble material in the first, or sealcoat layer is generally a“GI insoluble” or “GI partially insoluble” film forming polymer(dispersed or dissolved in a solvent). Examples include, but are notlimited to, ethyl cellulose, cellulose acetate, cellulose acetatebutyrate, polymethacrylates such as ethyl acrylate/methyl methacrylatecopolymer (Eudragit NE-30-D) and ammonio methacrylate copolymer types Aand B (Eudragit RL30D and RS30D) and silicone elastomers. Usually, aplasticizer is used together with the polymer. Exemplary plasticizersinclude, but are not limited to, dibutylsebacate, propylene glycol,triethylcitrate, tributylcitrate, castor oil, acetylated monoglycerides,acetyl triethylcitrate, acetyl butylcitrate, diethyl phthalate, dibutylphthalate, triacetin, fractionated coconut oil (medium-chaintriglycerides). The second layer containing the active ingredient may becomprised of the active ingredient with or without a polymer as abinder. The binder, when used, is usually hydrophilic but may bewater-soluble or water-insoluble. Exemplary polymers that may be used inthe second layer containing the active drug are hydrophilic polymerssuch as, for example, polyvinylpyrrolidone (PVP), polyalkylene glycolsuch as polyethylene glycol, gelatine, polyvinyl alcohol, starch andderivatives thereof, cellulose derivatives, such as hydroxypropylmethylcellulose (HPMC), hydroxypropyl cellulose, carboxymethyl cellulose,methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxyethylcellulose, carboxymethylhydroxyethyl cellulose, acrylic acid polymers,polymethacrylates, or any other pharmaceutically acceptable polymer. Theratio of drug to hydrophilic polymer in the second layer is usually inthe range of from 1:100 to 100:1 (w/w). Suitable polymers for use in thethird layer, or membrane, for controlling the drug release may beselected from water-insoluble polymers or polymers with pH-dependentsolubility, such as, for example, ethyl cellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, cellulose acetatetrimellitate, polymethacrylates, or mixtures thereof, optionallycombined with plasticizers, such as those mentioned above. Optionally,the controlled release layer comprises, in addition to the polymersabove, other substance(s) with different solubility characteristics, toadjust the permeability and thereby the release rate, of the controlledrelease layer. Exemplary polymers that may be used as a modifiertogether with, for example, ethyl cellulose include, but are not limitedto, HPMC, hydroxyethyl cellulose, hydroxypropyl cellulose,methylcellulose, carboxymethylcellulose, polyethylene glycol,polyvinylpyrrolidone (PVP), polyvinyl alcohol, polymers withpH-dependent solubility, such as cellulose acetate phthalate or ammoniomethacrylate copolymer and methacrylic acid copolymer, or mixturesthereof. Additives such as sucrose, lactose and pharmaceutical gradesurfactants may also be included in the controlled release layer, ifdesired.

The preparation of the multiple unit formulation comprises theadditional step of transforming the prepared beads into a pharmaceuticalformulation, such as by filling a predetermined amount of the beads intoa capsule, or compressing the beads into tablets. Examples ofmulti-particulate sustained release oral dosage forms are described in,for example, U.S. Pat. Nos. 6,627,223 and 5,229,135.

In other embodiments, an oral sustained release pump may be used (seeLanger, supra; Sefton, 1987, CRC Crit Ref Biomed. Eng. 14:201; Saudek etal., 1989, N. Engl. J Med. 321:574).

In still other embodiments, polymeric materials can be used (See“Medical Applications of Controlled Release,” Langer and Wise (eds.),CRC Press., Boca Raton, Fla. (1974); “Controlled Drug Bioavailability,”Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, NewYork (1984); Langer et al., 1983, J Macromol. Sci. Rev. Macromol Chem.23:61; see also Levy et al., 1985, Science 228: 190; During et al.,1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 71:105).In some embodiments, polymeric materials are used for oral sustainedrelease delivery. Polymers include, but are not limited to, sodiumcarboxymethylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose and hydroxyethylcellulose (especially,hydroxypropylmethylcellulose). Other cellulose ethers have beendescribed (Alderman, Int. J. Pharm. Tech. & Prod. Mfr. 1984, 5(3) 1-9).Factors affecting drug release are well known to the skilled artisan andhave been described in the art (Bamba et al., Int. J. Pharm. 1979, 2,307).

In other embodiments, enteric-coated preparations can be used for oralsustained release administration. Preferred coating materials includepolymers with a pH-dependent solubility (i.e., pH-controlled release),polymers with a slow or pH-dependent rate of swelling, dissolution orerosion (i.e., time-controlled release), polymers that are degraded byenzymes (i.e., enzyme-controlled release) and polymers that form firmlayers that are destroyed by an increase in pressure (i.e.,pressure-controlled release).

In yet other embodiments, drug-releasing lipid matrices can be used fororal sustained release administration. An example is when solidmicroparticles of a compound disclosed herein are coated with a thincontrolled release layer of a lipid (e.g., glyceryl behenate and/orglyceryl palmitostearate) as disclosed in Farah et al., U.S. Pat. No.6,375,987 and Joachim et al., U.S. Pat. No. 6,379,700. The lipid-coatedparticles can optionally be compressed to form a tablet. Anothercontrolled release lipid-based matrix material which is suitable forsustained release oral administration comprises polyglycolizedglycerides as disclosed in Roussin et at, U.S. Pat. No. 6,171,615.

In yet other embodiments, waxes can be used for oral sustained releaseadministration. Examples of suitable sustained compound-releasing waxesare disclosed in Cain et al., U.S. Pat. No. 3,402,240 (caranuba wax,candedilla wax, esparto wax and ouricury wax); Shtohryn et al., U.S.Pat. No. 4,820,523 (hydrogenated vegetable oil, bees wax, caranuba wax,paraffin, candelillia, ozokerite and mixtures thereof); and Walters,U.S. Pat. No. 4,421,736 (mixture of paraffin and castor wax).

In still other embodiments, osmotic delivery systems are used for oralsustained release administration (Verma et al., Drug Dev. Ind. Pharm.,2000, 26:695-708). In some embodiments, OROS® systems made by AlzaCorporation, Mountain View, Calif. are used for oral sustained releasedelivery devices (Theeuwes et al., U.S. Pat. No. 3,845,770; Theeuwes etal., U.S. Pat. No. 3,916,899).

In other embodiments, a controlled-release system can be placed inproximity of the target of a compound disclosed herein (e.g., within thespinal cord), thus requiring only a fraction of the systemic dose (See,e.g., Goodson, in “Medical Applications of Controlled Release,” supra,vol. 2, pp. 115-138 (1984)). Other controlled-release systems discussedin Langer, 1990, Science 249:1527-1533 may also be used.

In other embodiments, the dosage form comprises a compound disclosedherein coated on a polymer substrate. The polymer can be an erodible, ora nonerodible polymer. The coated substrate may be folded onto itself toprovide a bilayer polymer drug dosage form. For example, a compounddisclosed herein can be coated onto a polymer such as a polypeptide,collagen, gelatin, polyvinyl alcohol, polyorthoester, polyacetyl, or apolyorthocarbonate and the coated polymer folded onto itself to providea bilaminated dosage form. In operation, the bioerodible dosage formerodes at a controlled rate to dispense a compound disclosed herein overa sustained release period. Representative biodegradable polymerscomprise a member selected from the group consisting of biodegradablepoly(amides), poly (amino acids), poly(esters), poly(lactic acid),poly(glycolic acid), poly(carbohydrate), poly(orthoester), poly(orthocarbonate), poly(acetyl), poly(anhydrides), biodegradablepoly(dihydropyrans), and poly(dioxinones) which are known in the art(Rosoff, Controlled Release of Drugs Chap. 2, pp. 53-95 (1989); and inU.S. Pat. Nos. 3,811,444; 3,962,414; 4,066,747, 4,070,347; 4,079,038;and 4,093,709).

In other embodiments, the dosage form comprises a compound disclosedherein loaded into a polymer that releases the compound by diffusionthrough a polymer, or by flux through pores or by rupture of a polymermatrix. The drug delivery polymeric dosage form comprises between about10 mg to 500 mg of compound homogenously contained in or on a polymer.The dosage form comprises at least one exposed surface at the beginningof dose delivery. The non-exposed surface, when present, is coated witha pharmaceutically acceptable material impermeable to the passage of acompound. The dosage form may be manufactured by procedures known in theart. An example of providing a dosage form comprises blending apharmaceutically acceptable carrier like polyethylene glycol, with aknown dose of a compound at an elevated temperature, (e.g., 37° C.), andadding it to a silastic medical grade elastomer with a cross-linkingagent, for example, octanoate, followed by casting in a mold. The stepis repeated for each optional successive layer. The system is allowed toset for about 1 hour, to provide the dosage form. Representativepolymers for manufacturing the dosage form are selected from the groupconsisting of olefinic polymers, vinyl polymers, addition polymers,condensation polymers, carbohydrate polymer and silicone polymers asrepresented by polyethylene, polypropylene, polyvinyl acetate,polymethylacrylate, polyisobutylmethacrylate, poly alginate, polyamideand polysilicone. The polymers and procedures for manufacturing themhave been described in the art (Coleman et al., Polymers 1990, 31,1187-1231; Roerdink et al., Drug Carrier Systems 1989, 9, 57-10; Leonget al., Adv. Drug Delivery Rev. 1987, 1, 199-233; Roff et al, Handbookof Common Polymers 1971, CRC Press; and U.S. Pat. No. 3,992,518).

In other embodiments, the dosage from comprises a plurality of tinypills. The tiny time-release pills provide a number of individual dosesfor providing various time doses for achieving a sustained-releaseprodrug delivery profile over an extended period of time up to 24 hours.The matrix comprises a hydrophilic polymer selected from the groupconsisting of a polysaccharide, agar, agarose, natural gum, alkalialginate including sodium alginate, carrageenan, fucoidan, furcellaran,laminaran, hypnea, gum arabic, gum ghatti, gum karaya, grum tragacanth,locust bean gum, pectin, amylopectin, gelatin, and a hydrophiliccolloid. The hydrophilic matrix comprises a plurality of 4 to 50 tinypills, each tiny pill comprise a dose population of from 10 ng, 0.5 mg,1 mg, 1.2 mg, 1.4 mg, 1.6 mg, 5.0 mg, etc. The tiny pills comprise arelease rate-controlling wall of 0.001 mm up to 10 mm thickness toprovide for the timed release of a compound. Representative wall formingmaterials include a triglyceryl ester selected from the group consistingof glyceryl tristearate, glyceryl monostearate, glyceryl dipalmitate,glyceryl laureate, glyceryl didecenoate and glyceryl tridenoate. Otherwall forming materials comprise polyvinyl acetate, phthalate,methylcellulose phthalate and microporous olefins. Procedures formanufacturing tiny pills are disclosed in U.S. Pat. Nos. 4,434,153;4,721,613; 4,853,229; 2,996,431; 3,139,383 and 4,752,470.

In still other embodiments, the dosage form comprises an osmotic dosageform, which comprises a semipermeable wall that surrounds a therapeuticcomposition comprising the compound. In use within a patient, theosmotic dosage form comprising a homogenous composition, imbibes fluidthrough the semipermeable wall into the dosage form in response to theconcentration gradient across the semipermeable wall. The therapeuticcomposition in the dosage form develops osmotic pressure differentialthat causes the therapeutic composition to be administered through anexit from the dosage form over a prolonged period of time up to 24 hours(or even in some cases up to 30 hours) to provide controlled andsustained compound release. These delivery platforms can provide anessentially zero order delivery profile as opposed to the spikedprofiles of immediate release formulations.

In still other embodiments, the dosage form comprises another osmoticdosage form comprising a wall surrounding a compartment, the wallcomprising a semipermeable polymeric composition permeable to thepassage of fluid and substantially impermeable to the passage ofcompound present in the compartment, a compound-containing layercomposition in the compartment, a hydrogel push layer composition in thecompartment comprising an osmotic formulation for imbibing and absorbingfluid for expanding in size for pushing the compound composition layerfrom the dosage form, and at least one passageway in the wall forreleasing the prodrug composition. The method delivers the compound byimbibing fluid through the semipermeable wall at a fluid imbibing ratedetermined by the permeability of the semipermeable wall and the osmoticpressure across the semipermeable wall causing the push layer to expand,thereby delivering the compound from the dosage form through the exitpassageway to a patient over a prolonged period of time (up to 24 oreven 30 hours). The hydrogel layer composition may comprise 10 mg to1000 mg of a hydrogel such as a member selected from the groupconsisting of a polyalkylene oxide of 1,000,000 to 8,000,000weight-average molecular weight, which are selected from the groupconsisting of a polyethylene oxide of 1,000,000 weight-average molecularweight, a polyethylene oxide of 2,000,000 molecular weight, apolyethylene oxide of 4,000,000 molecular weight, a polyethylene oxideof 5,000,000 molecular weight, a polyethylene oxide of 7,000,000molecular weight and a polypropylene oxide of the 1,000,000 to 8,000,000weight-average molecular weight; or 10 mg to 1000 mg of an alkalicarboxymethylcellulose of 10,000 to 6,000,000 weight average molecularweight, such as sodium carboxymethylcellulose or potassiumcarboxymethylcellulose. The hydrogel expansion layer comprises 0.0 mg to350 mg, in present manufacture; 0.1 mg to 250 mg of ahydroxyalkylcellulose of 7,500 to 4,500,00 weight-average molecularweight (e.g., hydroxymethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, hydroxybutylcellulose or hydroxypentylcellulose)in present manufacture; 1 mg to 50 mg of an agent selected from thegroup consisting of sodium chloride, potassium chloride, potassium acidphosphate, tartaric acid, citric acid, raffinose, magnesium sulfate,magnesium chloride, urea, inositol, sucrose, glucose and sorbitol; 0 to5 mg of a colorant, such as ferric oxide; 0 mg to 30 mg, in a presentmanufacture, 0.1 mg to 30 mg of a hydroxypropylalkylcellulose of 9,000to 225,000 average-number molecular weight, selected from the groupconsisting of hydroxypropylethylcellulose, hydroxypropypentylcellulose,hydroxypropylmethylcellulose, and hydropropylbutylcellulose; 0.00 to 1.5mg of an antioxidant selected from the group consisting of ascorbicacid, butylated hydroxyanisole, butylated hydroxyquinone,butylhydroxyanisol, hydroxycoumarin, butylated hydroxytoluene, cephalm,ethyl gallate, propyl gallate, octyl gallate, lauryl gallate,propyl-hydroxybenzoate, trihydroxybutylrophenone, dimethylphenol,dibutylphenol, vitamin E, lecithin and ethanolamine; and 0.0 mg to 7 mgof a lubricant selected from the group consisting of calcium stearate,magnesium stearate, zinc stearate, magnesium oleate, calcium palmitate,sodium suberate, potassium laurate, salts of fatty acids, salts ofalicyclic acids, salts of aromatic acids, stearic acid, oleic acid,palmitic acid, a mixture of a salt of a fatty, alicyclic or aromaticacid, and a fatty, alicyclic, or aromatic acid.

In the osmotic dosage forms, the semipermeable wall comprises acomposition that is permeable to the passage of fluid and impermeable tothe passage of prodrug. The wall is nontoxic and comprises a polymerselected from the group consisting of a cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose acetate, cellulose diacetateand cellulose triacetate. The wall comprises 75 wt % (weight percent) to100 wt % of the cellulosic wall-forming polymer or, the wall cancomprise additionally 0.01 wt % to 80 wt % of polyethylene glycol, or 1wt % to 25 wt % of a cellulose ether selected from the group consistingof hydroxypropylcellulose or a hydroxypropylalkycellulose such ashydroxypropylmethylcellulose. The total weight percent of all componentscomprising the wall is equal to 100 wt %. The internal compartmentcomprises the compound-containing composition alone or in layeredposition with an expandable hydrogel composition. The expandablehydrogel composition in the compartment increases in dimension byimbibing the fluid through the semipermeable wall, causing the hydrogelto expand and occupy space in the compartment, whereby the drugcomposition is pushed from the dosage form. The therapeutic layer andthe expandable layer act together during the operation of the dosageform for the release of prodrug to a patient over time. The dosage formcomprises a passageway in the wall that connects the exterior of thedosage form with the internal compartment. The osmotic powered dosageform can be made to deliver prodrug from the dosage form to the patientat a zero order rate of release over a period of up to about 24 hours.

The expression “passageway” as used herein comprises means and methodssuitable for the metered release of the compound from the compartment ofthe dosage form. The exit means comprises at least one passageway,including orifice, bore, aperture, pore, porous element, hollow fiber,capillary tube, channel, porous overlay, or porous element that providesfor the osmotic controlled release of compound. The passageway includesa material that erodes or is leached from the wall in a fluidenvironment of use to produce at least one controlled-releasedimensioned passageway. Representative materials suitable for forming apassageway, or a multiplicity of passageways comprise a leachablepoly(glycolic) acid or poly(lactic) acid polymer in the wall, agelatinous filament, poly(vinyl alcohol), leach-able polysaccharides,salts, and oxides. A pore passageway, or more than one pore passageway,can be formed by leaching a leachable compound, such as sorbitol, fromthe wall. The passageway possesses controlled-release dimensions, suchas round, triangular, square and elliptical, for the metered release ofprodrug from the dosage form. The dosage form can be constructed withone or more passageways in spaced apart relationship on a single surfaceor on more than one surface of the wall. The expression “fluidenvironment” denotes an aqueous or biological fluid as in a humanpatient, including the gastrointestinal tract. Passageways and equipmentfor forming passageways are disclosed in U.S. Pat. Nos. 3,845,770;3,916,899; 4,063,064; 4,088,864 and 4,816,263. Passageways formed byleaching are disclosed in U.S. Pat. Nos. 4,200,098 and 4,285,987.

Regardless of the specific form of sustained release oral dosage formused, compounds are preferably released from the dosage form over aperiod of at least about 6 hours, more preferably, over a period of atleast about 8 hours, and most preferably, over a period of at leastabout 12 hours. Further, the dosage form preferably releases from 0 to30% of the prodrug in 0 to 2 hours, from 20 to 50% of the prodrug in 2to 12 hours, from 50 to 85% of the prodrug in 3 to 20 hours and greaterthan 75% of the prodrug in 5 to 18 hours. The sustained release oraldosage form further provides a concentration of baclofen or baclofenanalog in the blood plasma of the patient over time, which curve has anarea under the curve (AUC) that is proportional to the dose of theprodrug of baclofen or baclofen analog administered, and a maximumconcentration C_(max). The C_(max) is less than 75%, and is preferably,less than 60%, of the C_(max) obtained from administering an equivalentdose of the compound from an immediate release oral dosage form and theAUC is substantially the same as the AUC obtained from administering anequivalent dose of the prodrug from an immediate release oral dosageform.

Preferred dosage forms are administered once or twice per day, morepreferably, once per day.

4.6 Therapeutic Uses of Compounds, Compositions and Dosage Forms

In some embodiments, a therapeutically effective amount of one or morecompounds of Formulae (I), (V) or (VI) is administered to a patient,preferably a human, suffering from stiffness, involuntary movementsand/or pain associated with spasticity. The underlying etiology of thespasticity being so treated may have a multiplicity of origins,including, e.g., cerebral palsy, multiple sclerosis, stroke and head andspinal cord injuries. In other embodiments, a therapeutically effectiveamount of one or more compounds of Formulae (I), (V) or (VI) isadministered to a patient, preferably a human, suffering fromgastro-esophageal reflux disease. In still other embodiments, atherapeutically effective amount of one or more compounds of Formulae(I), (V) or (VI) is administered to a patient, preferably a human,suffering from emesis. In still other embodiments, a therapeuticallyeffective amount of one or more compounds of Formulae (I), (V) or (VI)is administered to a patient, preferably, a human, suffering from cough.In still other embodiments, a therapeutically effective amount of one ormore compounds of Formulae (I), (V) or (VI) is administered to apatient, preferably a human, suffering from drug addiction. Addiction tostimulants such as cocaine or amphetamines, or narcotics such asmorphine or heroin may be effectively treated by administration of oneor more compounds of Formulae (I), (V) or (VI). In yet otherembodiments, a therapeutically effective amount of one or more compoundsof Formulae (I), (V) or (VI) is administered to a patient, preferably ahuman, suffering from alcohol abuse or addiction and nicotine abuse oraddiction. In some of the above embodiments, sustained release oraldosage forms are administered to the patients.

Further, in certain embodiments, a therapeutically effective amount ofone or more compounds of Formulae (I), (V) or (VI) are administered to apatient, preferably a human, as a preventative measure against variousdiseases or disorders. Thus, the therapeutically effective amount of oneor more compounds of Formulae (I), (V) or (VI) may be administered as apreventative measure to a patient having a predisposition forspasticity, gastro-esophageal reflux disease, emesis, cough, alcoholaddiction or abuse, nicotine abuse or addiction or other drug addictionor abuse.

When used to treat or prevent the above diseases or disorders thetherapeutically effective amount of one or more compounds of Formulae(I), (V) or (VI) may be administered or applied singly, or incombination with other agents. The therapeutically effective amount ofone or more compounds of Formulae (I), (V) or (VI) may also deliver acompound disclosed herein in combination with another pharmaceuticallyactive agent, including another compound disclosed herein. For example,in the treatment of a patient suffering from gastro-esophageal refluxdisease, a dosage form comprising a compound of Formulae (I), (V) or(VI) may be administered in conjunction with a proton pump inhibitor,such as omeprazole, esomeprazole, pantoprazole, lansoprazole orrabeprazole sodium, or with an H₂ antagonist such as rantidine,cimetidine or famotidine.

Dosage forms, upon releasing the baclofen or baclofen analog prodrug,preferably provide baclofen or baclofen analogs upon in vivoadministration to a patient. While not wishing to bound by theory, thepromoiety or promoieties of the prodrug may be cleaved either chemicallyand/or enzymatically. One or more enzymes present in the stomach,intestinal lumen, intestinal tissue, blood, liver, brain or any othersuitable tissue of a mammal may enzymatically cleave the promoiety orpromoieties of the prodrug. If the promoiety or promoieties are cleavedafter absorption by the gastrointestinal tract, these baclofen orbaclofen analog prodrugs may have the opportunity to be absorbed intothe systemic circulation from the large intestine. It is preferred thatthe promoiety or promoieties are cleaved after absorption by thegastrointestinal tract.

4.7 Doses

Baclofen and baclofen analog prodrugs are administered to treat orprevent diseases or disorders such as spasticity, gastro-esophagealreflux disease, emesis, cough, alcohol, nicotine or other drugaddiction.

The amount of baclofen or baclofen analog prodrug that will be effectivein the treatment of a particular disorder or condition disclosed hereinwill depend on the nature of the disorder or condition, and can bedetermined by standard clinical techniques known in the art. Inaddition, in vitro or in vivo assays may optionally be employed to helpidentify optimal dosage ranges. The amount of a compound administeredwill, of course, be dependent on, among other factors, the subject beingtreated, the weight of the subject, the severity of the affliction, themanner of administration and the judgment of the prescribing physician.

Preferably, the dosage forms are adapted to be administered to a patientno more than twice per day, more preferably, only once per day. Dosingmay be provided alone or in combination with other drugs and maycontinue as long as required for effective treatment of the diseasestate or disorder.

Suitable dosage ranges for oral administration are dependent on thepotency of the parent baclofen analog. For baclofen doses are generallybetween about 0.15 mg to about 2.5 mg per kilogram body weight. Otherbaclofen analogs may be more potent and lower doses may be appropriatefor both the parent drug and any prodrug (measured on an equivalentmolar basis). For example, doses of R-baclofen prodrugs that areequivalent (on a molar basis) to R-baclofen doses of between about 0.03mg to about 1 mg per kilogram body weight are appropriate. Dosage rangesmay be readily determined by methods known to the skilled artisan.

5. Examples

The following examples describe in detail preparation of compounds andcompositions disclosed herein and assays for using compounds andcompositions disclosed herein. It will be apparent to those of ordinaryskill in the art that many modifications, both to materials and methods,may be practiced.

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

-   -   Boc=tert-butyloxycarbonyl    -   Cbz=carbobenzyloxy    -   DCC=dicyclohexylcarbodiimide    -   DMAP=4-N,N-dimethylaminopyridine    -   DMF=N,N-dimethylformamide    -   DMSO=dimethylsulfoxide    -   Fmoc=9-fluorenylmethyloxycarbonyl    -   g=gram    -   h=hour    -   HPLC=high pressure liquid chromatography    -   L=liter    -   LC/MS=liquid chromatography/mass spectroscopy    -   M=molar    -   min=minute    -   mL=milliliter    -   mmol=millimoles    -   THF=tctrahydrofuran    -   TFA=trifluoroacetic acid    -   TLC=thin layer chromatography    -   TMS=trimethylsilyl    -   μL=microliter    -   μM=micromolar    -   v/v=volume to volume

Example 1: 4-tert-Butoxycarbonylamino-(3R)-(4-chlorophenol)-butanoicAcid (5)

To a stirred solution containing (R)-baclofen hydrochloride (2.34 g,9.36 mmol) and NaOH (0.97 g, 24.34 mmol) in a mixture of dioxane andwater (1:1) was added a solution of di-tert-butyl dicarbonate (2.65 g,12.16 mmol) in dioxane (10 mL). The resulting solution was stirred atambient temperature for 40 min. Then the reaction mixture wasconcentrated on a rotary evaporator to remove most of dioxane, theresidue was extracted with ether to remove excess di-tert-butyldicarbonate and the aqueous phase was acidified to pH˜3 with saturatedcitric acid solution to precipitate a white solid. The precipitate wasfiltered, washed with water, dried in a desiccator in vacuo to affordthe title compound (5) as a white fluffy powder (2.4 g, 82%). ¹H NMR(CDCl₃, 400 MHz): δ 1.40 (s, 9H), 2.56 (dd, 1H), 2.68 (dd, 1H), 3.26 (m,2H), 3.40 (m, 1H), 7.14 (d, 2H), 7.27 (d, 2H).

Example 2: Benzyl4-tert-Butoxycarbonylamino-(3R)-(4-chlorophenyl)-butanoate (6)

To a stirred solution of compound (5) (1.41 g, 4.49 mmol) and benzylbromide (0.769 g, 4.49 mmol) in DMF was added Cs₂CO₃ (1.46 g, 4.49 mmol)at ambient temperature. The resulting suspension was stirred for 3 h,with the reaction progress monitored by TLC and/or LC/MS. The reactionmixture was poured into ice-water, extracted with ethyl acetate and thecombined organic phase was washed with water and brine, dried overanhydrous Na₂SO₄ and concentrated in vacuo to afford the title compound(6) as a white solid (1.69 g, 94%). ¹H NMR (CDCl₃, 400 MHz): δ 1.39 (s,9H), 2.61 (dd, 1H), 2.74 (dd, 1H), 3.30 (m, 2H), 3.40 (m, 1H), 4.46 (brs, 1H), 4.99 (s, 2H), 7.07-7.35 (m, 9H).

Example 3: Benzyl 4-Amino-(3R)-(4-chlorophenyl)-butanoate Hydrochloride(7)

Compound (6) (1.69 g, 4.19 mmol) was dissolved in a 4N solution of HClin dioxane and the resulting reaction mixture stirred at roomtemperature for 40 min. The reaction mixture was diluted with ether, theresulting precipitate was filtered off, washed with ether and hexane,and dried in vacuo to afford the title compound (7) (1.39 g, 98%). ¹HNMR (CD₃OD, 400 MHz): δ 2.72 (dd, 1H), 2.86 (dd, 1H), 3.12 (m, 1H), 3.27(m, 1H), 3.47 (m, 1H), 5.01 (s, 2H), 7.06-7.30 (m, 9H). MS (ESI) m/z304.19 (M+H)⁺.

Example 4: Benzyl4-(Chloromethoxy)carbonylamino-(3R)-(4-chlorophenyl)-butanoate (8)

To a stirred suspension of compound (7) (500 mg, 1.47 mmol) in CH₂Cl₂(20 mL) at 0° C. was added N-methylmorpholine (0.404 mL, 3.67 mmol). Theresulting mixture was stirred at 0° C. until a clear solution wasobtained. Then 1-chloromethyl chloroformate (199 mg, 1.544 mmol) inCH₂Cl₂ (1 mL) was added and the reaction mixture was stirred at 0° C.with TLC monitoring. After 40 minutes, the reaction was diluted withCH₂Cl₂, washed with citric acid solution and brine and dried overanhydrous Na₂SO₄. The solvent was removed in vacuo to afford the titlecompound (8) (430 mg, 74%). ¹H NMR (CDCl₃, 400 MHz): δ 2.64 (dd, 1H),2.74 (dd, 1H), 3.49 (m, 2H), 3.53 (m, 1H), 4.92 (br. s, 1H), 5.01 (s,2H), 5.66 (AB q, 2H), 7.07-7.30 (m, 9H).

Example 5: Benzyl4-[(Acetoxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate

To a suspension of Ag₂CO₃ (417 mg, 1.514 mmol) and acetic acid (0.170mL, 3.028 mmol) in CHCl₃ (2 mL) was added a solution of compound (8)(300 mg, 0.757 mmol) in CHCl₃ (1 mL). The resulting suspension wasstirred at room temperature for 24 h. The reaction mixture was thendiluted with CH₂Cl₂, filtered through a pad of Celite, and the filtratewashed with 10% aqueous NaHCO₃ solution and brine, then dried overanhydrous Na₂SO₄. After removal of the solvent in vacuo, the residue waspurified by flash chromatography on silica gel, eluting with a gradientof 15%-30% ethyl acetate in hexane to afford the title compound (9) (280mg, 88%). ¹H NMR (CDCl₃, 400 MHz): δ 2.05 (s, 3H), 2.62 (m, 1H), 2.70(m, 1H), 3.33 (m, 2H), 3.47 (m, 1H), 4.99 (m, 3H), 5.62 (s, 2H),7.08-7.28 (m, 9H).

Example 6: Sodium4-[(Acetoxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate (10)

A solution of compound (9) (80 mg, 0.190 mmol) in ethanol (20 mL) wasstirred with 10% Pd on carbon (8 mg) in a 50 mL round-bottomed flaskunder an atmosphere of hydrogen gas (balloon). The reaction was judgedcomplete in 30 min. (monitoring by LC/MS). The mixture was filteredthrough a pad of Celite, and the solvent removed in vacuo to afford thecrude product, which was purified by preparatory LC/MS to give theproduct in its protonated acid form (46 mg, 73%). ¹H NMR (CD₃OD, 400MHz): δ 2.04 (s, 3H), 2.57 (m, 1H), 2.72 (m, 1H), 3.31 (m, 3H), 5.61 (s,2H), 7.22-7.28 (m, 4H). MS (ESI) m/z 328.13 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 equiv.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (10).

Example 7: Benzyl4-[(Benzoyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(11)

Following the procedure of Example 5 and replacing acetic acid withbenzoic acid, compound (11) was obtained in 72% yield. ¹H NMR (CDCl₃,400 MHz): δ 2.62 (dd, 1H), 2.72 (dd, 1H), 3.33 (m, 2H), 3.50 (m, 1H),4.98 (br. s, 3H), 5.90 (s, 2H), 7.05 (d, 2H), 7.12-7.28 (m, 7H), 7.56(t, 1H), 7.41 (t, 2H), 8.03 (d, 2H).

Example 8: Sodium4-[(Benzoyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(12)

Following the procedure of Example 6 and replacing compound (9) withcompound (11) afforded the product in its protonated acid form in 69%yield. ¹H NMR (CD₃OD, 400 MHz): δ 2.57 (m, 1H), 2.71 (m, 1H), 3.33 (m,3H), 5.89 (AB q, 2H), 7.20 (m, 4H), 7.50 (t, 2H), 7.63 (t, 1H), 8.00 (d,2H). MS (ESI) m/z 390.15 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 equiv.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (12).

Example 9: Benzyl4-[(Cyclohexaneearboxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(13)

Following the procedure of Example 5 and replacing acetic acid withcyclohexane carboxylic acid, compound (13) was obtained in 38% yield. ¹HNMR (CDCl₃, 400 MHz): δ 1.20-1.42 (m, 5H), 1.62-1.87 (m, 5H), 2.29 (m,1H), 2.61 (m, 1H), 2.71 (m, 1H), 3.32 (m, 2H), 3.48 (m, 1H), 4.99 (s,2H), 5.12 (br. s, 1H), 5.64 (m, 2H), 7.06-7.28 (m, 9H).

Example 10: Sodium4-[(Cyclohexanecarboxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(14)

Following the procedure of Example 6 and replacing compound (9) withcompound (13) afforded the product in its protonated acid form in 40%yield. ¹H NMR (CDCl₃, 400 MHz): δ 1.20-1.40 (m, 5H), 1.63-1.93 (m, 5H),2.35 (m, 1H), 2.70 (m, 2H), 3.36 (m, 2H), 3.54 (m, 1H), 5.02 (br. m,1H), 5.69 (m, 2H), 7.15 (d, 2H), 7.28 (d, 2H). MS (ESI) m/z 396.18(M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 equiv.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (14).

Example 11: Benzyl4-[(Butanoyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(15)

Following the procedure of Example 5 and replacing acetic acid withn-butyric acid, compound (15) was obtained. ¹H NMR (CDCl₃, 400 MHz): δ0.93 (t, 3H), 1.63 (m, 2H), 2.30 (t, 2H), 2.64 (m, 1H), 2.74 (m, 1H),3.33 (m, 2H), 3.49 (m, 1H), 4.91 (br. s, 1H), 5.00 (s, 2H), 5.65 (m,2H), 7.06-7.30 (m, 9H).

Example 12: Sodium4-[(Butanoyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(16)

Following the procedure of Example 6 and replacing compound (9) withcompound (15) afforded the product in its protonated acid form in 40%yield. ¹H NMR (CDCl₃, 400 MHz): δ 0.94 (t, 3H), 1.64 (m, 2H), 2.32 (t,2H), 2.65 (m, 2H), 3.35 (m, 2H), 3.52 (m, 1H), 5.00 (br. s, 1H), 5.67(s, 2H), 7.11-7.29 (m, 4H). MS (ESI) m/z 356.19 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 equiv.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (16).

Example 13: Benzyl

4-[(Isobutanoyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(17)

Following the procedure of Example 5 and replacing acetic acid withisobutyric acid, compound (17) was obtained in 22% yield. ¹H NMR (CDCl₃,400 MHz): δ 1.15 (m, 6H), 2.55 (m, 1H), 2.62 (dd, 1H), 2.72 (dd, J=1H),3.33 (m, 2H), 3.48 (m, 1H), 4.83 (br. s, 1H), 4.99 (s, 2H), 5.65 (s,2H), 7.06-7.30 (m, 9H).

Example 14: Sodium4-[(Isobutanoyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(18)

Following the procedure of Example 6 and replacing compound (9) withcompound (17) afforded the product in its protonated acid form in 80%yield. ¹H NMR (CDCl₃, 400 MHz): δ 1.16 (m, 6H), 2.60 (m, 1H), 2.71 (m,1H), 3.35 (m, 2H), 3.51 (m, 1H), 5.03 (br. t, 1H), 5.67 (s, 2H), 7.12(d, 2H), 7.26 (d, 2H). MS (ESI) m/z 356.15 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 equiv.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (18).

Example 15: Benzyl4-[(Pivaloyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(19)

Following the procedure of Example 5 and replacing acetic acid withpivalic acid, compound (19) was obtained in 36% yield. ¹H NMR (CDCl₃,400 MHz): δ 1.17 (s, 9H), 2.62 (dd, 1H), 2.72 (dd, 1H), 3.33 (m, 2H),3.48 (m, 1H), 4.84 (br. t, 1H), 5.00 (s, 2H), 5.65 (s, 2H), 7.06-7.30(in, 9H).

Example 16: Sodium

4-[(Pivaloyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(20)

Following the procedure of Example 6 and replacing compound (9) withcompound (19) afforded the product in its protonated acid form in 75%yield. ¹H NMR (CDCl₃, 400 MHz): δ 1.19 (s, 9H), 2.60 (dd, 1H), 2.68 (dd,1H), 3.34 (m, 2H), 3.51 (m, 1H), 5.01 (br. t, 1H), 5.66 (s, 2H), 7.11(m, 2H), 7.26 (m, 2H). MS (ESI) m/z 370.22 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 equiv.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (20).

Example 17: Benzyl4-[(1-Chloroisobutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(21)

To a stirred suspension of compound (7) (900 mg, 2.64 mmol) in CH₂Cl₂(50 mL) at 0° C. was added N-methylmorpholine (0.97 mL, 8.82 mmol). Theresulting mixture was stirred at 0° C. until a clear solution wasobtained. Then 1-chloro-2-methylpropyl chloroformate (474 mg, 2.77 mmol)in CH₂Cl₂ (1 mL) was added and the solution stirred at 0° C. for 3 h(TLC monitoring). The reaction mixture was diluted with CH₂Cl₂, washedwith citric acid solution and brine, then dried over anhydrous Na₂SO₄.Removal of the solvent in vacuo afforded the title compound (21) as apair of diastereomers (932 mg, 80%). ¹H NMR (CDCl₃, 400 MHz): δ 0.99 (d,3H), 1.02 (d, 3H), 2.10 (m, 1H), 2.64 (dd, 1H), 2.74 (dd, 1H), 3.33 (m,2H), 3.53 (m, 1H), 4.80 (br. s, 1H), 5.01 (s, 2H), 6.24 (d, 1H),7.07-7.30 (m, 9H).

Example 18: Benzyl4-[(1-Acetoxyisobutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(22)

To a solution of compound (21) (246 mg, 0.561 mmol) in CH₂Cl₂ (0.5 mL)was added acetic acid (0.32 mL, 5.61 mmol) and N-methylmorpholine (0.31mL, 2.8 mmol). The resulting mixture was stirred for 48 h at roomtemperature. The reaction then was diluted with CH₂Cl₂, washedsuccessively with water, 10% aqueous NaHCO₃ solution, dilute citric acidsolution and brine, then dried over anhydrous Na₂SO₄. After removal ofthe solvent in vacuo, the residue was purified by flash chromatographyon silica gel, eluting with a gradient of 10%-20% ethyl acetate inhexane to afford the title compound (22) as a pair of diastereomers (120mg, 46%). ¹H NMR (CDCl₃, 400 MHz): δ 0.92 (m, 6H), 2.10 (m, 4H), 2.75(m, 2H), 3.45 (m, 3H), 4.68 (br. s, 1H), 5.00 (s, 2H), 6.44 (m, 1H),7.02-7.33 (m, 91-1).

Example 19: Sodium4-[(1-Acetoxyisobutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(23)

Following the procedure of Example 6 and replacing compound (9) withcompound (22), the product in protonated acid form was obtained as apair of diastereomers. ¹H NMR (CDCl₃, 400 MHz): δ 0.92 (m, 6H), 1.93 (m,1H), 2.05 (s, 3H), 2.65 (m, 2H), 3.33 (m, 2H), 3.49 (m, 1H), 4.70 (br.s., 1H), 6.50 (m, 1H), 7.10 (m, 2H), 7.26 (m, 2H). MS (ESI) m/z 370.20(M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 equiv.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (23).

Example 20: Benzyl4-[(1-Isobutanoyloxyisobutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(24)

To a solution of compound (21) (50 mg, 0.114 mmol) in isobutyric acid(0.5 mL, 5.39 mmol) was added N-methylmorpholine (0.57 mmol). Afterstirring the mixture overnight at 50° C., the reaction mixture wasdiluted with CH₂Cl₂, washed successively with water, 10% aqueous NaHCO₃solution and brine and then dried over anhydrous Na₂SO₄. After removalof the solvent in vacuo, the title compound (24) was obtained as a pairof diastereomers (40 mg, 72%). ¹H NMR (CDCl₃, 400 MHz): δ 0.91 (m, 6H),1.17 (m, 6H), 1.96 (m, 1H), 2.54 (m, 1H), 2.63 (m, 1H), 2.73 (m, 1H),3.31 (m, 2H), 3.48 (m, 1H), 4.68 (br. s, 1H), 6.52 (m, 1H), 7.07-7.29(m, 9H).

Example 21: Sodium4-[(1-Isobutanoyloxyisobutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(25)

Following the procedure of Example 6 and replacing compound (9) withcompound (24), the product in protonated acid form was obtained as apair of diastereomers in 50% yield. ¹H NMR (CDCl₃, 400 MHz): δ 0.92 (m,6H), 1.16 (m, 6H), 1.97 (m, 1H), 2.51-2.74 (m, 3H), 3.33 (m, 3H), 6.50(d, 1H), 7.10 (d, 2H), 7.27 (d, 2H). MS (ESI) m/z 398.18 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 equiv.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (25).

Example 22: Benzyl4-[(1-Butanoyloxyisobutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(26)

Following the procedure of Example 20 and replacing isobutyric acid withn-butyric acid, the title compound (26) was obtained as a pair ofdiastereomers (90 mg, 80%). ¹H NMR (CDCl₃, 400 MHz): δ 0.92 (m, 9H),1.64 (m, 2H), 1.96 (m, 1H), 2.27 (m, 2H), 2.61 (m, 1H), 2.74 (m, 1H),3.32 (m, 2H), 3.48 (m, 1H), 4.76 (br. s, 1H), 6.53 (m, 1H), 7.06-7.28(m, 9H).

Example 23: Sodium4-[(1-Butanoyloxyisobutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(27)

Following the procedure of Example 6 and replacing compound (9) withcompound (26), the product in protonated acid form was obtained as apair of diastereomers in 75% yield. ¹H NMR (CDCl₃, 400 MHz): δ 0.92 (m,9H), 1.65 (m, 2H), 1.96 (m, 1H), 2.29 (t, 2H), 2.66 (m, 2H), 3.25-3.59(m, 3H), 4.72 (br. d, 1H), 6.52 (d, 1H), 7.11 (d, 2H), 7.26 (d, 2H). MS(ESI) m/z 398.24 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 equiv.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (27).

Example 24: Benzyl4-[(1-Chloroethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate (28)

Following the procedure of Example 17 and replacing1-chloro-2-methylpropyl chloroformate with 1-chloroethyl chloroformate,the title compound (28) was obtained as a pair of diastereomers in 67%yield. ¹H NMR (CDCl₃, 400 MHz):

1.71 (d, 3H), 2.63 (dd, 1H), 2.73 (dd, 1H), 3.32 (m, 2H), 3.49 (m, 1H),5.00 (m, 3H), 6.48 (q, 1H), 7.07 (d, 2H), 7.14-7.28 (m, 7H).

Example 25: Benzyl4-[(1-Acetoxyethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate (29)

To a stirred solution of compound (28) (183 mg, 0.446 mmol) in CH₂Cl₂ (5mL) was added acetic acid (0.26 mL, 4.46 mmol) and N-methylmorpholine(0.25 mL, 2.23 mmol), and the resulting reaction mixture was stirred atroom temperature for 48 h. The mixture was diluted with CH₂Cl₂, washedsuccessively with water, 10% aqueous NaHCO₃ solution and brine, thendried over anhydrous Na₂SO₄. After removal of the solvent in vacuo, theresidue was purified by flash chromatography on silica gel, eluting witha gradient of 10%-20% ethyl acetate in hexane to afford the titlecompound (29) as a pair of diastereomers (110 mg, 57%). ¹H NMR (CDCl₃,400 MHz): δ 1.41 (m, 3H), 2.03 (m, 3H), 2.61 (m, 1H), 2.72 (m, 1H), 3.33(m, 2H), 3.49 (m, 1H), 4.82 (br. s, 1H), 5.00 (s, 2H), 6.74 (m, 1H),7.13 (m, 2H), 7.17-7.28 (m, 7H).

Example 26: Sodium4-[(1-Acetoxyethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate (30)

Following the procedure of Example 6 and replacing compound (9) withcompound (29), the product in its protonated acid form was obtained as apair of diastereomers in 57% yield. ¹H NMR (CDCl₃, 400 MHz): δ 1.42 (m,3H), 2.02 (m, 3H), 2.62 (m, 1H), 2.71 (m, 1H), 3.32 (m, 2H), 3.49 (m,1H), 4.80 (br. s, 1H), 6.74 (m, 1H), 7.13 (m, 2H), 7.27 (m, 2H). MS(ESI) m/z 342.24 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 equiv.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (30).

Example 27: Benzyl4-[(1-Butanoyloxyethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(31)

Following the procedure of Example 25 and replacing acetic acid withn-butyric acid, the title compound (31) was obtained as a pair ofdiastereomers (109 mg, 68%). ¹H NMR (CDCl₃, 400 MHz): δ 0.94 (m, 3H),1.42 (m, 3H), 1.64 (m, 2H), 2.27 (m, 2H), 2.60 (m, 1H), 2.71 (m, 1H),3.31 (m, 2H), 3.50 (m, 1H), 4.80 (br. s, 1H), 5.00 (s, 2H), 6.75 (m,1H), 7.11 (d, 2H), 7.15-7.28 (m, 7H).

Example 28: Sodium4-[(1-Butanoyloxyethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(32)

Following the procedure of Example 6 and replacing compound (9) withcompound (31), the product in its protonated acid form was obtained as apair of diastereomers in 75% yield. ¹H NMR (CDCl₃, 400 MHz): δ 0.94 (m,3H), 1.42 (m, 3H), 1.64 (m, 2H), 2.27 (m, 2H), 2.60 (m, 1H), 2.71 (m,1H), 3.31 (m, 2H), 3.50 (m, 1H), 4.82 (br. s, 1H), 6.75 (m, 1H), 7.11(d, 2H), 7.27 (d, 2H). MS (ESI) m/z 370.27 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 equiv.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (32).

Example 29: Sodium4-[(1-Isobutanoyloxyethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(33)

To a suspension of R-baclofen hydrochloride (500 mg, 1.47 mmol) inCH₂Cl₂ at 0° C. was added triethylamine (0.9 mL, 6.4 mmol) and a 1Nsolution of chlorotrimethylsilane in CH₂Cl₂ (3.23 mL, 3.23 mmol). Theresulting reaction mixture was stirred at 0° C. for 10 min, then wasadded 1-isobutanoyloxyethyl-p-nitrophenyl carbonate (577 mg, 1.94 mmol,prepared as described in Gallop et al., U.S. Patent Appl. Publ.2003/0176398, in CH₂Cl₂. The reaction mixture was stirred at roomtemperature for 3 h (monitoring by LC/MS) and then diluted with CH₂Cl₂,washed with citric acid solution and brine, and dried over anhydrousNa₂SO₄. After removal of solvent in vacuo, the residue was purified byflash chromatography on silica gel, eluting first with CH₂Cl₂ to removep-nitrophenol, then with 20% ethyl acetate in hexane to afford theproduct in its protonated acid form as a pair of diastereomers (400 mg,73%). ¹H NMR (CDCl₃, 400 MHz): δ 1.13 (m, 6H), 1.40 (m, 3H), 2.51 (m,1H), 2.57 (dd, 1H), 2.71 (dd, 1H), 3.32 (m, 2H), 3.47 (m, 1H), 4.89 (br.s, 1H), 6.72 (q, 1H), 7.11 (d, 2H), 7.26 (d, 2H). MS (ESI) m/z 370.15(M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 equiv.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (33).

Example 30: Asymmetric Synthesis of Sodium 4-{[(1S)-Isobutanoyloxyethoxy1-carbonylamino}-(3R)-(4-chlorophenyl)-butanoate (34) Step A: Synthesisof4-{[(1S)-Isobutanoylethoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoicAcid (35)

To a solution of (4S)-hydroxy-2-methylpentan-3-one (200 mg, 1.67 mmol)in CH₂Cl₂ (10 mL) at 0° C. was added p-nitrophenyl chloroformate (336 mg1.67 mmol), pyridine (0.135 mL, 1.67 mmol) and 4-dimethylaminopyridine(61 mg, 0.5 mmol). The resulting mixture was stirred at 0° C. for 1 h,then allowed to warm to room temperature overnight. The reaction mixturewas then added to a suspension containing R-baclofen hydrochloride (500mg, 1.47 mmol), chlorotrimethylsilane (2.94 mmol) and triethylamine(5.99 mmol) in CH₂Cl₂ at 0° C. The reaction was stirred at roomtemperature for 5 h, then diluted with CH₂Cl₂, washed successively withwater, 10% aqueous NaHCO₃ solution, dilute citric acid solution andbrine, then dried over anhydrous Na₂SO₄. After filtration and removal ofthe solvent in vacuo, the crude product was purified by preparatoryLC/MS to afford compound (35) (230 mg, 44%). ¹H NMR (CDCl₃, 400 MHz): δ1.06 (d, 3H), 1.12 (d, 3H), 1.32 (d, 3H), 2.60 (m, 1H), 2.75 (m, 2H),3.29 (m, 2H), 3.44 (m, 1H), 5.13 (q, 1H), 7.13 (m, 2H), 7.26 (m, 2H). MS(ESI) m/z 354.10 (M−H)⁻.

Step B: Synthesis of Sodium4-{[(1S)-Isobutanoyloxyethoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoate(34)

To a solution of compound (35) (179 mg, 0.503 mmol) in CH₂Cl₂ (5 mL) at0° C. was added NaHCO₃ (42 mg, 0.503 mmol) and m-chloroperbenzoic acid(174 mg, 1.00 mmol). The resulting suspension was stirred at 0° C. toroom temperature for 24 h, then an additional aliquot ofm-chloroperbenzoic acid (174 mg, 1.00 mmol) was added to the reaction.The mixture was allowed to stir at room temperature for a further 24 h,then diluted with CH₂Cl₂, filtered through a pad of Celite, and thefiltrate washed with water and brine, then dried over anhydrous Na₂SO₄.After filtration and removal of the solvent in vacuo, the crude productwas purified by preparatory LC/MS to afford the product in itsprotonated acid form as a single diastereomer (24 mg, 14%). ¹H NMR(CDCl₃, 400 MHz): δ 1.15 (d, 6H), 1.40 (d, 3H), 2.51 (hept, 1H), 2.59(dd, 1H), 2.70 (dd, 1H), 3.30 (m, 2H), 3.50 (m, 1H), 4.94 (br. s, 1H),6.72 (q, 1H), 7.12 (d, 2H), 7.26 (d, 2H). MS (ESI) m/z 370.15 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 equiv.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (34).

Example 31: Benzyl4-[(1-Pivaloylethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate (35)

To a stirred solution of compound (28) (500 mg, 1.22 mmol) in THF (5 mL)was added pivalic acid (1.24 g, 12.1 mmol) and N-methylmorpholine (0.7mL, 6.05 mmol), and the resulting reaction mixture was stirred at 50° C.for 48 hours. The reaction mixture was diluted with ethyl acetate,washed successively with water, 10% aqueous NaHCO₃ solution and brine,then dried over anhydrous Na₂SO₄. After removal of solvent in vacuo, theresidue was purified by flash chromatography on silica gel, eluting witha gradient of 5-10% ethyl acetate in hexane to afford the title compound(35) as a pair of diastereomers (252 mg, 44%). ¹H NMR (CDCl₃, 400 MHz):δ 1.15 (s, 3H), 1.17 (s, 6H), 1.40 (q, 3H), 2.62 (dd, 1H), 2.74 (dd,1H), 3.25 (m, 2H), 3.46 (m, 1H), 4.82 (br.t, 1H), 4.99 (s, 2H), 6.71 (m,1H), 7.29-7.07 (m. 9H).

Example 32: Sodium4-[(1-Pivaloylethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate (36)

Following the procedure of Example 6 and replacing compound (9) withcompound (35), the product in its protonated acid form was obtained as apair of diasteromers in 76% yield. ¹H NMR (CDCl₃, 400 MHz): δ 1.16 (s,3H), 1.18 (s, 6H), 1.40 (d, 3H), 2.59 (dd, 1H), 3.31 (m, 2H), 3.48 (m,1H), 3.70 (dd, 1H), 4.82 (m, 1H), 6.70 (m, 1H), 7.12 (d, 2H), 7.26 (d,2H). MS (ESI) m/z 384.18 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (36).

Example 33: Benzyl4-[(1-Cyclohexylcarbonyloxyethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(37)

To a stirred solution of compound (28) (500 mg, 1.22 mmol) in THE (5 mL)was added cyclohexanecarboxylic acid (1.56 g, 12.14 mmol) andN-methylmorpholine (0.7 mL, 6.05 mmol), and the resulting reactionmixture was stirred at 45° C. for 48 hours. The reaction mixture wasdiluted with ethyl acetate, washed successively with water, 10% aqueousNaHCO₃ solution and brine, then dried over anhydrous Na₂SO₄. Afterremoval of solvent in vacuo, the residue was purified by flashchromatography on silica gel, eluting with a gradient of 5-10% ethylacetate in hexane to afford the title compound (37) as a pair ofdiastereomers (348 mg, 57%). ¹H NMR (CDCl₃, 400 MHz): δ 1.22 (m, 3H),1.39 (m, 5H), 1.61 (m, 1H), 1.72 (m, 2H), 1.85 (m, 2H), 2.24 (m, 1H),2.62 (dd, 1H), 2.73 (dd, 1H), 3.30 (m, 2H), 3.46 (m, 1H), 4.90 (br. m,1H), 4.98 (s, 2H), 6.73 (m, 1H), 7.07-7.28 (m, 9H).

Example 34: Sodium4-[(1-Cyclohexylcarbonyloxyethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(38)

Following the procedure of Example 6 and replacing compound (9) withcompound (37), the product in its protonated acid form was obtained as apair of diasteromers in 38% yield. ¹H NMR (CDCl₃, 400 MHz): δ 1.24 (m,3H), 1.40 (m, 5H), 1.63 (m, 1H), 1.74 (m, 2H), 1.86 (m, 2H), 2.27 (m,1H), 2.59 (dd, 1H), 2.70 (dd, 1H), 3.31 (m, 2H), 3.48 (m, 1H), 4.79 (br.d, 1H), 6.72 (q, 1H), 7.11 (d, 2H), 7.25 (d, 2H). MS (ESI) m/z 410.21(M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO3 (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (38).

Example 35: Benzyl4-[(1-Benzoyloxyethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(39)

Following the synthesis procedure for compound (37) and replacingcyclohexanecarboxylic acid with benzoic acid, the title compound (39)was obtained as a pair of diastereomers in 69% yield. ¹H NMR (CDCl₃, 400MHz): δ 1.54 (q, 3H), 2.62 (m, 1H), 2.74 (dd, 1H), 3.31 (m, 2H), 3.48(m, 1H), 4.92 (br. s, III), 4.97 (s, 2H), 7.01 (q, 1H), 7.27-7.05 (m,10H), 7.39 (m, 2H), 7.52 (m, 1H), 7.98 (m, 2H).

Example 36: Sodium4-[(1-Benzoyloxyethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(40)

Following the procedure of Example 6 and replacing compound (9) withcompound (39), the product in its protonated acid form was obtained as apair of diasteromers in 74% yield. NMR (CDCl₃, 400 MHz): δ 1.56 (t, 3H),2.59 (m, 1H), 2.71 (m, 1H), 3.33 (m, 2H), 3.49 (m, 1H), 7.01 (q, 1H),7.10 (d, 2H), 7.25 (dd, 2H), 7.42 (t, 2H), 7.55 (t, 1H), 8.02 (t, 2H).MS (ESI) m/z 404.17 (m-H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO3 (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (40).

Example 37: Benzyl4-[(1-Benzoyloxyisobutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(41)

To a stirred solution of compound (21) (0.634 g, 1.45 mmol) in THF (5mL) was added benzoic acid (1.76 g, 14.5 mmol) and N-methylmorpholine(0.73 g, 7.23 mmol), and the resulting reaction mixture was stirred at50° C. for 48 hours. The reaction mixture was diluted with ethylacetate, washed successively with water, 10% aqueous NaHCO₃ solution andbrine, then dried over anhydrous Na₂SO₄. After removal of solvent invacuo, the residue was purified by flash chromatography on silica gel,eluting with a gradient of 5%-10 ethyl acetate in hexane to afford thetitle compound (41) as a pair of diastereomers (0.59 g, 45%). ¹H NMR(CDCl₃, 400 MHz): δ 1.02 (m, 6H), 2.10 (m, 1H), 2.63 (m, 1H), 2.74 (m,1H), 3.32 (m, 2H), 3.49 (m, 1H), 4.79 (t, 1H), 4.98 (d, 2H), 6.78 (t,1H), 7.07 (d, 2H), 7.18 (m, 4H), 7.27 (m, 3H), 7.40 (m, 2H), 7.56 (m,1H), 8.01 (t, 2H).

Example 38: Sodium4-[(1-Benzoyloxyisobutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(42)

Following the procedure of Example 6 and replacing compound (9) withcompound (41), the product in its protonated acid form was obtained as apair of diasteromers in 59% yield. ¹H NMR (CDCl₃, 400 MHz): δ 8.02 (d,2H), 7.56 (t, 1H), 7.43 (t, 3H), 7.21 (d, 2H), 7.11 (d, 2H), 6.77 (d,1H), 4.71 (m, 1H), 3.54 (m, 1H), 3.31 (m. 2H), 2.72 (m, 1H), 2.60 (m,1H), 0.2.11 (m, 1H), 1.00 (m, 6H). MS (ESI) m/z 432.25 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (42).

Example 39: Sodium4-[(1-Pivaloyloxyisobutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(43) Step A: O-(1-Chloroisobutoxy) S-Ethyl Thiocarbonate (44)

To a stirred solution of ethanethiol (1.23 mL, 16.7 mmol) andtriethylamine (2.93 mL, 21.1 mmol) in CH₂Cl₂ at 0° C. was added1-chloro-2-methylpropyl chloroformate (3.0 g, 17.5 mmol). The resultingmixture was stirred for 10 min. at 0° C., and then the reaction mixturewas diluted with CH₂Cl₂, washed successively with dilute HCl and brine,then dried over anhydrous Na₂SO₄. After concentration in vacuo the crudeO-(1-chloroisobutoxy) S-ethyl thiocarbonate (44) was obtained, and useddirectly in the next step without further purification. ¹H NMR (CDCl₃,400 MHz): δ 1.05 (t, 6H), 1.35 (t, 3H), 2.17 (m, 1H), 2.90 (q, 2H), 6.33(d, 1H).

Step B: O-(1-Pivaloyloxyisobutoxy) S-Ethyl Thiocarbonate (45)

A mixture of (44) (936 mg, 4.76 mmol), pivalic acid (2.43 g, 23.8 mmol)and N,N-diisopropylethylamine (2.40 g, 23.8 mmol) was stirred at 75° C.for four days, and the reaction was judged complete by ¹H-NMR. Thereaction mixture was cooled to room temperature and portioned betweenwater and ether, the ether phase was washed successively with water,aqueous NaHCO₃, and brine, then dried over anhydrous Na₂SO₄. Afterrotary evaporation, the crude O-(1-pivaloyloxyisobutoxy) S-ethylthiocarbonate (45) was obtained in quantitative yield, and used in thenext step without further purification. ¹H NMR (CDCl₃, 400 MHz): δ 0.96(d, 6H), 1.21 (d, 9H), 1.30 (t, 3H), 2.03 (m, 1H), 6.65 (d, 1H).

Step C: (1-Pivaloyloxyisobutoxy) Chloroformate (46)

A solution of (45) (4.76 mmol) in CH₂Cl₂ at 0° C. was treated withsulfuryl chloride (1.1 mmol) under N₂ for 10 min, then the reactionmixture was concentrated to dryness in vacuo to afford the crudechloroformate (46) in quantitative yield, which used in the next stepwithout further purification. ¹H NMR (CDCl₃, 400 MHz): δ 1.00 (d, 6H),1.20 (d, 9H), 2.143 (m, 1H), 6.54 (d, 1H).

Step D: [(1-Pivaloyloxyisobutoxy)carbonyloxy]Succinimide (47)

To a solution of N-hydroxysuccinimide (1.2 eq.) and pyridine (2.4 eq.)in CH₂Cl₂ at 0° C. was added an equimolar solution of the abovechloroformate (46) in CH₂Cl₂. The resulting reaction mixture was stirredat 0° C. for 1 h, then was washed successively with water, dilute HCland brine, then dried over Na₂SO₄. After removal of the solvent invacuo, the crude N-hydroxysuccinimidyl carbonate (47) was obtained inquantitative yield, and was used in the next step without furtherpurification.

Step E: Sodium4-[(1-Pivaloyloxyisobutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(43)

To a stirred solution of R-baclofen (1 g, 4.69 mmol) and NaHCO₃ (394 mg,4.69 mmol) in water was added a solution of (47) (4.69 mmol) inacetonitrile. The resulting reaction mixture was stirred at roomtemperature for 1 h, then acidified to pH 5 with 10% HCl, extracted withethyl acetate, washed with brine, and dried over anhydrous Na₂SO₄. Thesolvent was removed in vacuo to afford the crude product, which waspurified by preparative LC/MS to afford 146 mg of the product in itsacid form. ¹H NMR (CDCl₃, 400 MHz): δ 0.88 (m, 6H), 1.15 (d, 9H), 1.92(m, 1H), 2.54 (m, 1H), 2.67 (m, 1H), 3.27 (m, 2H), 3.42 (m, 1H), 4.83(t, 1H), 7.08 (d, 2H), 7.21 (d, 2H). MS (ESI) m/z 412.30 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (43).

Example 40: Sodium4-[(1-Propanoyloxyisobutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(48)

Following the procedures of Example 39 and replacing pivalic acid withpropionic acid in Step B afforded the title compound in its acid form.¹H NMR (CDCl₃, 400 MHz): δ 0.90 (m, 6H), 1.14 (t, 3H), 1.96 (m, 1H),2.33 (m, 2H), 2.64 (m, 1H), 2.72 (m, 1H), 3.52-3.28 (m, 3H), 4.69 (m,1H), 6.51 (d, 1H), 7.12 (m, 2H), 7.27 (m, 2H). MS (ESI) m/z 384.10(M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (48).

Example 41: Sodium4-[(1-Cyclopentylcarbonyloxyisobutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(49)

Following the procedures of Example 39 and replacing pivalic acid withcyclopentanecarboxylic acid in Step B afforded the title compound in itsacid form. ¹H NMR (CDCl₃, 400 MHz): δ 0.91 (m, 6H), 1.53-1.98 (m, 9H),2.56-2.74 (m, 3H), 3.31 (m, 2H), 3.45 (m, 1H), 4.71 (m, 1H), 6.49 (d,1H), 7.10 (q, 2H), 7.24 (m, 2H). MS (ESI) m/z 424.11 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (49).

Example 42: Sodium4-[(1-Cyclohexylcarbonyloxyisobutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(50)

Following the procedures of Example 39 and replacing pivalic acid withcyclohexanecarboxylic acid in Step B afforded the title compound in itsacid form. ¹H NMR (CDCl₃, 400 MHz): δ 0.89 (m, 6H), 1.22 (m, 3H), 1.40(m, 2H), 1.61 (m, 1H), 1.70 (m, 2H), 1.89 (m, 3H), 2.27 (m, 1H), 2.58(m, 1H), 2.70 (m, 1H), 3.29 (m, 2H), 3.23 (m, 1H), 4.73 (br.s, 1H), 6.48(m, 1H), 7.10 (dd, 2H), 7.24 (dd, 2H). MS (ESI) m/z 438.14 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (50).

Example 43: Sodium4-[(2,2-Diethoxypropanoyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(51) Step A: Benzyl4-[(2,2-Diethoxypropanoyloxymethoxy)-carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(52)

A suspension of compound (8) (230 mg, 0.528 mmol) and cesium2,2-diethoxypropionate (233 mg, 0.792 mmol) in DMF was stirred at 40° C.for 1 h then cooled to room temperature. The reaction mixture waspartitioned between ice-water and ethyl acetate, and the organic phasewas washed with brine, dried over anhydrous Na₂SO₄, and concentrated invacuo to afford the crude product, which was purified by chromatographyon silica gel, eluting with a mixture of 20% ethyl acetate in hexane togive the title compound (52). ¹H NMR (CDCl₃, 400 MHz): δ 1.18-1.27 (m,6H), 2.68 (m, 1H), 2.80 (m, 1H), 3.33-3.58 (m, 7H), 4.99 (m, 3H), 5.75(s, 2H), 7.08-7.29 (m, 9H).

Step B: Sodium4-[(2,2-Diethoxypronanoyloxymethoxy)-carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(a)

Following the procedure of Example 6 and replacing compound (9) with(52) afforded the title compound in its acid form. ¹H NMR (CDCl₃, 400MHz): δ 1.20 (t, 6H), 2.59 (dd, 1H), 2.69 (dd, 1H), 3.31-3.61 (m, 7H),5.15 (m, 1H), 5.76 (s, 2H), 7.11 (d, 2H), 7.26 (d, 2H). MS (ESI) m/z430.14 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (51).

Example 44: Sodium4-[(4-Methoxybenzoyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(53)

Following the same procedures of Example 39 but replacing1-chloro-2-methylpropyl chloroformate with chloromethyl chloroformate inStep A and replacing pivalic acid with p-anisic acid in Step B affordedthe title compound in its acid form. ¹H NMR (CDCl₃, 400 MHz): δ 2.60(dd, 1H), 2.70 (dd, 1H), 3.33 (m, 2H), 3.50 (m, 1H), 3.83 (s, 3H), 5.24(m, 1H), 5.87 (s, 2H), 6.88 (d, 2H), 7.09 (d, 2H), 7.20 (d, 2H), 7.96(d, 2H). MS (ESI) m/z 420.11 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (53).

Example 45: Sodium4-[(Nicotinoyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(54)

Following the same procedures of Example 39 but replacing1-chloro-2-methylpropyl chloroformate with chloromethyl chloroformate inStep A and replacing pivalic acid with nicotinic acid in Step B affordedthe title compound in its acid form. ¹H NMR (CD₃OD 400 MHz): δ 2.55 (dd,1H), 2.70 (dd, 1H), 3.29 (m, 3H), 5.90 (s, 2H), 7.19 (m, 5H), 7.55 (dd,1H), 8.35 (d, 1H), 8.74 (dd, 1H), 9.09 (s, 1H). MS (ESI) m/z 393.11(M+H)⁺.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (54).

Example 46: Sodium

4-[(Cyclopentylcarbonyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(55)

Following the same procedures of Example 39 but replacing1-chloro-2-methylpropyl chloroformate with chloromethyl chloroformate inStep A and replacing pivalic acid with cyclopentanecarboxylic acid inStep B afforded the title compound in its acid form.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (55). ¹H NMR (CD₃OD 400 MHz): δ 1.57-1.88 (m.8H), 2.54 (m, 1H), 2.72 (m, 2H), 3.29 (m, 3H), 5.61 (q, 2H), 7.23 (m,4H). MS (ESI) m/z 381.91 (M−H)⁻.

Example 47: Sodium4-[(2-Furoyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(56)

Following the same procedures of Example 39 but replacing1-chloro-2-methylpropyl chloroformate with chloromethyl chloroformate inStep A and replacing pivalic acid with 2-furoic acid in Step B affordedthe title compound in its acid form.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (56). ¹H NMR (CD₃OD 400 MHz): δ 2.37 (dd, 1H),2.52 (dd, 1H), 3.29 (m, 3H), 5.77 (q, 2H), 6.61 (d, 1H), 7.20 (m, 4H),7.23 (d, 1H), 7.76 (d, 1H). MS (ESI) m/z 379.99 (M−H)⁻.

Example 48: Sodium4-[(2-Thienylcarbonyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate (57)

Following the same procedures of Example 39 but replacing1-chloro-2-methylpropyl chloroformate with chloromethyl chloroformate inStep A and replacing pivalic acid with thiophene-2-carboxylic acid inStep B afforded the title compound in its acid form.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (57). ¹H NMR (CD₃OD 400 MHz): δ 2.39 (dd, 1H),2.52 (dd, 1H), 3.30 (m, 3H), 5.80 (AB q, 2H), 7.16 (m, 5H), 7.80 (m,2H). MS (ESI) m/z 419.77 (M+Na)⁺.

Example 49: Sodium

4-[(Phenylacetoxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(58)

Following the same procedures of Example 39 but replacing1-chloro-2-methylpropyl chloroformate with chloromethyl chloroformate inStep A and replacing pivalic acid with phenylacetic acid in Step Bafforded the title compound in its acid form.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (58). ¹H NMR (CD₃OD 400 MHz): δ 2.38 (dd, 1H),2.51 (dd, 1H), 3.29 (m, 3H), 5.61 (AB q, 2H), 7.24 (m, 9H). MS (ESI) m/z403.91 (M−H)⁻.

Example 50: Sodium4-[(3-Methylbutanoyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(59)

Following the same procedures of Example 39 but replacing1-chloro-2-methylpropyl chloroformate with chloromethyl chloroformate inStep A and replacing pivalic acid with isovaleric acid in Step Bafforded the title compound in its acid form.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (59). ¹H NMR (CD₃OD 400 MHz): δ 0.94 (d, 6H),2.03 (m, 1H), 2.19 (d, 2H), 2.53 (m, 1H), 2.70 (m, 1H), 3.29 (m, 3H),5.62 (AB q, 2H), 7.23 (m, 4H). MS (ESI) m/z 394.03 (M+Na)⁺.

Example 51: Sodium4-[(Pentanoyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(60)

Following the same procedures of Example 39 but replacing1-chloro-2-methylpropyl chloroformate with chloromethyl chloroformate inStep A and replacing pivalic acid with valeric acid in Step B affordedthe title compound in its acid form.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (60). ¹H NMR (CD₃OD 400 MHz): δ 0.91 (t, 3H),1.33 (m, 2H), 1.56 (p, 2H), 2.31 (t, 2H), 2.42 (m, 1H), 2.56 (m, 1H),3.30 (m, 3H), 5.59 (AB q, 2H), 7.22 (m, 4H). MS (ESI) m/z 394.15(M+Na)⁺.

Example 52: Sodium4-[(Cinnamoyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(61)

Following the same procedures of Example 39 but replacing1-chloro-2-methylpropyl chloroformate with chloromethyl chloroformate inStep A and replacing pivalic acid with cinnamic acid in Step B affordedthe title compound in its acid form.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (61). ¹H NMR (CD₃OD 400 MHz): δ 2.39 (dd, 1H),2.53 (d, 1H), 3.29 (m, 3H), 5.72 (AB q, 2H), 6.49 (d, 1H), 7.21 (m, 4H),7.31 (m, 3H), 7.61 (m, 2H), 7.72 (d, 1H). MS (ESI) m/z 440.14 (M±Na)⁺.

Example 53: Sodium4-[(3-Phenylpropionoyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(62)

Following the same procedures of Example 39 but replacing1-chloro-2-methylpropyl chloroformate with chloromethyl chloroformate inStep A and replacing pivalic acid with dihydrocinnamic acid in Step Bafforded the title compound in its acid form.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (62). ¹H NMR (CD₃OD 400 MHz): δ 2.39 (dd, 1H),2.52 (dd, 1H), 2.61 (t, 2H), 2.88 (t, 2H), 3.29 (m, 3H), 5.58 (s, 2H),7.21 (m, 9H). MS (ESI) m/z 442.14 (M+Na)⁺.

Example 54: Sodium4-[(2-Methylbutanoyloxymethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(63)

Following the same procedures of Example 39 but replacing1-chloro-2-methylpropyl chloroformate with chloromethyl chloroformate inStep A and replacing pivalic acid with 2-methylbutyric acid in Step Bafforded the title compound in its acid form.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (63) as a pair of diasteromers. ¹H NMR (CD₃OD400 MHz): δ 0.87 (dt, 3H), 1.08 (dd, 3H), 1.44 (m, 1H), 1.60 (m, 1H),2.36 (m, 2H), 2.50 (m, 1H), 3.29 (m, 3H), 5.60 (AB q, 2H), 7.21 (m, 4H).MS (ESI) m/z 394.04 (M+Na)⁺.

Example 55: Sodium4-[(1-Cyclopentanecarbonyloxybutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(64) Step A: 1-Chlorobutyl Chloroformate (65)

To a solution of triphosgene (4.94 g, 16.6 mmol) and n-butyraldehyde(3.0 g, 41.6 mmol) in anhydrous ether (30 mL) at 0° C. was addedpyridine (0.67 mL, 8.32 mmol) dropwise. The resulting suspension wasstirred at 0° C. for 30 min. The reaction mixture was filtered through apad of Celite and the supernatant was concentrated on a rotaryevaporator, affording the title chloroformate (4.38 g, 62%), which wasused in the next step without further purification. ¹H NMR (CDCl₃, 400MHz): δ 0.95 (t, 3H), 1.51 (m, 2H), 2.04 (m, 2H), 6.30 (t, 1H).

Step B: O-(1-Chlorobutoxy) S-Ethyl Thiocarbonate (66)

To a solution of ethanethiol (1.8 mL, 24.3 mmol) and triethylamine (4.3mL, 30.7 mmol) in CH₂Cl₂ at 0° C. was added chloroformate (65) (4.38 g,25.6 mmol) in CH₂Cl₂. The resulting reaction mixture was stirred for 10min at 0° C., then was washed successively with water, dilute HCl andbrine. The organic phase was dried over anhydrous Na₂SO₄. Afterconcentration in vacuo the crude O-(1-chlorobutoxy) S-ethylthiocarbonate (66) (3.99 g) was obtained, and used directly in the nextstep without further purification. ¹H NMR (CDCl₃, 400 MHz): δ 0.96 (t,3H), 1.34 (t, 3H), 1.50 (m, 2H), 2.00 (m, 2H), 2.90 (m, 2H), 6.47 (t,2H).

Step C:O-(1-Cyclopentanecarbonyloxybutoxy) S-Ethyl Thiocarbonate (67)

A mixture of (66) (1.33 g, 6.76 mmol) and cyclopentancarboxylic acid(1.30 g, 10.1 mmol) was stirred at 75° C. for five days. The reactionwas then cooled to room temperature and partitioned between water andether. The ether layer was washed with brine, dried over anhydrousNa₂SO₄. Filtration then removal of the solvent by rotary evaporationgave the title thiocarbonate (67) (1.62 g, 86%). ¹H NMR (CDCl₃, 400MHz): δ 0.95 (t, 3H), 1.20-1.85 (m, 15H), 2.68 (m, 1H), 2.82 (m, 2H).6.84 (t, 1H).

Step D: [(1-Cyclopentanecarbonyloxybutoxy)carbonyloxyl]Succinimide (68)

A solution of (67) (1.83 g, 6.34 mmol) in CH₂Cl₂ at 0° C. was treatedwith sulfuryl chloride (0.62 mL, 7.61 mmol) under N₂ for 10 min, thenthe reaction mixture was concentrated to dryness in vacuo to affordcrude (1-cyclopentanecarbonyloxy-butoxy) chloroformate in quantitativeyield. The chloroformate was dissolved in CH₂Cl₂, and was added to amixture of N-hydroxysuccinimide (1.09 g, 9.51 mmol) and pyridine (1.28mL, 15.8 mmol) in CH₂Cl₂ at 0° C. The reaction mixture was stirred at 0°C. for 1 h, then was washed with water, dilute HCl and brine and driedover Na₂SO₄. After removal of solvent in vacuo the titleN-hydroxysuccinimidyl carbonate (68) was obtained in quantitative yield,and was used in the subsequent step without further purification.

Step E: Sodium4-[(1-Cyclopentanecarbonyloxybutoxy)-carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(64)

To a solution of R-baclofen (644 mg, 3.02 mmol) and NaHCO₃ (323 mg,3.848 mmol) in water at room temperature was added a solution of (68)(900 mg, 2.749 mmol) in acetonitrile. The resulting reaction mixture wasstirred for 1 h at that temperature, then was acidified to pH 4 with 10%HCl, and extracted with ethyl acetate. The combined organic phase waswashed with brine and dried over anhydrous Na₂SO₄. Filtration andremoval of the solvent in vacuo gave the crude product, which waspurified by preparative LC/MS to afford the acid form of the titlecompound as a pair of diastereomers (636 mg, 75%).

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (1 mL) and then addition of aqueous NaHCO₃ (1 eq.) with sonicationfor 10 min. The solvent was removed by lyophilization to afford thetitle compound (64). ¹H NMR (CD₃OD, 400 MHz): δ 0.92 (m, 3H), 1.36 (m,2H), 1.56-1.87 (m, 10H), 2.41 (m, 1H), 2.52 (m, 1H), 2.70 (m, 1H), 3.29(m, 3H), 6.59 (q, 1H), 7.22 (m, 4H). MS (ESI) m/z 448.7 (M+Na)⁺.

Example 56: Sodium4-[(1-Cyclohexanecarbonyloxybutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(69)

Following the same procedures of Example 55 but replacingcyclopentanecarboxylic acid with cyclohexanecarboxylic acid afforded thetitle compound (69) as a pair of diastereomers (596 mg). ¹H NMR (CD₃OD,400 MHz): δ 0.94 (m, 3H), 1.33 (m, 7H), 1.61-1.83 (m, 7H), 2.26 (m, 1H),2.41 (m, 1H), 2.51 (m, 1H), 3.30 (m, 3H), 6.59 (m, 1H), 7.21 (m, 4H). MS(ESI) m/z 462.76 (M−Na)⁺.

Example 57: Sodium4-[(1-Hexanoyloxybutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(70)

Following the same procedures of Example 55 but replacingcyclopentanecarboxylic acid with hexanoic acid afforded the titlecompound (70) as a pair of diastereomers (894 mg). ¹H NMR (CD₃OD, 400MHz): δ 0.92 (m, 6H), 1.31 (m, 6H), 1.55-1.70 (m, 4H), 2.64 (m, 2H),2.40 (m, 1H), 2.53 (m, 1H), 3.30 (m, 3H), 6.61 (m, 1H), 7.22 (s, 4H). MS(ESI) m/z 450.76 (M+Na)⁺.

Example 58: Sodium4-[(1-Benzoyloxybutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(71)

Following the same procedures of Example 55 but replacingcyclopentanecarboxylic acid with benzoic acid afforded the titlecompound (71) as a pair of diastereomers (100 mg). ¹H NMR (CDCl₃, 400MHz): δ 0.71 (m, 3H), 1.14 (m, 2H), 1.48 (m, 2H), 2.72 (m, 2H), 3.35 (m,2H), 3.50 (m, 1H), 5.32 (br.m, 1H), 6.80 (m, 5H), 7.22 (m, 2H), 7.40 (m,1H), 7.75 (m, 2H). MS (ESI) m/z 456.10 (M+Na)⁺.

Example 59: Sodium4-[(1-Isobutanoyloxybutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(72)

Following the same procedures of Example 55 but replacingcyclopentanecarboxylic acid with isobutyric acid afforded the titlecompound (72) as a pair of diastereomers (70 mg). ¹H NMR (CDCl₃, 400MHz): δ 0.92 (m, 3H), 1.14 (m, 6H), 1.35 (m, 2H), 1.68 (m, 2H),2.48-2.72 (m, 3H), 3.25-3.52 (m, 3H), 4.73 (br. m, 1H), 6.65 (t, 1H),7.11 (d, 2H), 7.25 (d, 2H). MS (ESI) m/z 422.14 (M+Na)⁺.

Example 60: Sodium4-[(1-Butanoyloxybutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(73)

Following the same procedures of Example 55 but replacingcyclopentanecarboxylic acid with n-butyric acid afforded the titlecompound (73) as a pair of diastereomers (122 mg). ¹H NMR (CDCl₃, 400MHz): δ 0.85 (m, 6H), 1.24 (m, 2H), 1.52 (m, 4H), 2.14 (m, 2H), 2.35 (m,2H), 3.03-3.23 (2H), 3.35 (m, 1H), 5.40 (br.s, 1H), 6.61 (m, 1H), 6.98(d, 2H), 7.08 (m, 2H). MS (ESI) m/z 422.14 (M+Na)^(÷).

Example 61: Sodium4-[(1-Acetoxybutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate (74)

Following the same procedures of Example 55 but replacingcyclopentanecarboxylic acid with acetic acid afforded the title compound(74) as a pair of diastereomers (600 mg). ¹H NMR (CD₃OD, 400 MHz): δ0.92 (m, 3H), 135 (m, 2H), 1.67 (m, 2H), 1.99 (2s, 3H), 2.55 (m, 1H),2.70 (m, 1H), 3.29 (m, 3H), 6.60 (q, 1H), 7.25 (m, 4H). MS (ESI) m/z394.20 (M+Na)⁺.

Example 62: Sodium4-[(1-Propionyloxybutoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate

Following the same procedures of Example 55 but replacingcyclopentanecarboxylic acid with propionic acid afforded the titlecompound (75) as a pair of diastereomers (405 mg). ¹H NMR (CD₃OD, 400MHz): δ 0.93 (m, 3H), 1.08 (m, 3H), 1.33 (m, 2H), 1.64 (m, 2H),2.22-2.33 (m, 2H), 2.39 (m, 1H), 2.50 (m, 1H), 2.30 (m, 3H), 6.60 (m,1H), 7.22 (s, 4H). MS (ESI) m/z 408.11 (M+Na)⁺.

Example 63: Sodium4-[(1-Cyclohexanecarbonyloxypropoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(76)

Following the same procedures of Example 55 but replacing butyraldehydewith propionaldehyde in Step A and replacing cyclopentanecarboxylic acidwith cyclohexanecarboxylic acid in Step C afforded the title compound(76) as a pair of diastereomers (700 mg). ¹H NMR (CD₃OD, 400 MHz): δ0.87 (m, 3H), 1.25-1.39 (m, 5H), 1.62-1.86 (m, 7H), 2.1-2.54 (m, 3H),3.29 (m, 3H), 6.51 (m, 1H), 7.21 (m, 4H). MS (ESI) m/z 448.20 (M+Na)⁺.

Example 64: Sodium4-[(1-Isobutanoyloxypropoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(77)

Following the same procedures of Example 63 but replacingcyclohexanecarboxylic acid with isobutyric acid afforded the titlecompound (77) as a pair of diastereomers (140 mg). ¹H NMR (CD₃OD, 400MHz): δ 0.86-0.92 (m, 3H), 1.06-1.13 (m, 6H), 1.69 (m, 2H), 2.36-2.55(m, 3H), 3.30 (m, 3H), 6.51 (m, 1H), 7.22 (s, 4H). MS (ESI) m/z 408.11(M+Na)⁺.

Example 65: Sodium4-[(1-Butanoyloxypropoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(78)

Following the same procedures of Example 63 but replacingcyclohexanecarboxylic acid with n-butyric acid afforded the titlecompound (78) as a pair of diastereomers (1.09 g). ¹H NMR (CD₃OD, 400MHz): δ 0.91 (m, 6H), 1.59 (m, 2H), 1.69 (m, 2H), 2.23-2.25 (m, 2H),2.40 (m, 1H), 2.51 (m, 1H), 3.29 (m, 3H), 6.56 (q, 1H), 7.22 (s, 4H). MS(ESI) m/z 408.73 (M+Na)⁺.

Example 66: Sodium4-[(1-Propionoyloxypropoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(79)

Following the same procedures of Example 63 but replacingcyclohexanecarboxylic acid with propionic acid afforded the titlecompound (79) as a pair of diastereomers (100 mg). ¹H NMR (CD₃OD, 400MHz): δ 0.88 (m, 3H), 1.08 (m, 3H), 2.21 (m, 1H), 2.25 (m, 2H), 2.39 (m,1H), 2.50 (m, 1H), 3.30 (m, 3H), 6.52 (q, 1H), 7.22 (s, 4H). MS (ESI)m/z 394.08 (M+Na)⁺.

Example 67: Sodium4-[(1-Pivaloyloxypropoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(80)

Following the same procedures of Example 63 but replacingcyclohexanecarboxylic acid with pivalic acid afforded the title compound(80) as a pair of diastereomers (420 mg). ¹H NMR (CD₃OD, 400 MHz): δ0.90 (m, 3H), 1.10 (s, 4.5 H), 1.16 (s, 4.5 H), 1.70 (m, 2H), 2.47-2.55(m, 2H), 3.30 (m, 3H), 6.50 (dt, 1H), 7.22 (s, 4H). (ESI) m/z 422.07(M+Na)⁺.

Example 68: Sodium4-[(1-Benzoyloxypropoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(81)

Following the same procedures of Example 63 but replacingcyclohexanecarboxylic acid with benzoic acid afforded the title compound(81) as a pair of diastereomers (129 mg). ¹H NMR (CD₃OD, 400 MHz): δ0.98 (m, 3H), 1.85 (m, 2H), 2.39 (m, 1H), 2.52 (m, 1H), 3.30 (m, 3H),6.78 (m, 1H), 7.18 (m, 4H), 7.48 (m, 2H), 7.60 (m, 1H), 7.95 (m, 2H). MS(ESI) m/z 442.07 (M+Na)⁺.

Example 69: Sodium4-[(1-Acetoxy-1-cyclohexylmethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(82)

Following the same procedures of Example 55 but replacing butyraldehydewith cyclohexanecarboxaldehyde in Step A and replacingcyclopentanecarboxylic acid with acetic acid in Step C afforded thetitle compound (82) as a pair of diastereomers (759 mg). ¹H NMR (CD₃OD,400 MHz): δ 0.94-1.28 (m, 4H), 1.60-1.80 (m, 6H), 1.98 (s, 1.5H), 2.01(s, 1.5H), 2.39 (m, 1H), 2.51 (m, 1H), 3.30 (m, 3H), 6.40 (M, 1H), 7.22(s, 4H). MS (ESI) m/z 434.73 (M+Na)⁺.

Example 70: Sodium4-[(1-Propionyloxy-1-cyclohexylmethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate83)

Following the same procedures of Example 55 but replacing butyraldehydewith cyclohexanecarboxaldehyde in Step A and replacingcyclopentanecarboxylic acid with propionic acid in Step C afforded thetitle compound (83) as a pair of diastereomers (310 mg). ¹H NMR (CD₃OD,400 MHz): δ 0.96-1.30 (m, 7H), 1.58-1.80 (m, 6H), 2.24-2.42 (m, 3H),2.53 (m, 1H), 3.30 (m, 3H), 6.42 (q, 1H), 7.21 (s, 4H). MS (ESI) m/z448.10 (M+Na)⁺.

Example 71: Sodium4-[(1-Isobutanoyloxy-1-cyclohexylmethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(84)

Following the same procedures of Example 55 but replacing butyraldehydewith cyclohexanecarboxaldehyde in Step A and replacingcyclopentanecarboxylic acid with isobutyric acid in Step C afforded thetitle compound (84) as a pair of diastereomers (800 mg). ¹H NMR (CD₃OD,400 MHz): δ 0.96-1.28 (m, 10H), 1.58-1.79 (m, 6H), 2.36-2.54 (m, 3H),3.30 (m, 3H), 7.21 (s, 4H). MS (ESI) m/z 462.21 (M+Na)⁺.

Example 72: Sodium4-[(1-Butanoyloxy-1-cyclohexylmethoxy)carbonylamino]-(3R)-(4-chlorophenyl)-butanoate(85)

Following the same procedures of Example 55 but replacing butyraldehydewith cyclohexanecarboxaldehyde in Step A and replacingcyclopentanecarboxylic acid with n-butyric acid in Step C afforded thetitle compound (85) as a pair of diastereomers (520 mg). ¹H NMR (CD₃OD,400 MHz): δ 0.92 (m, 3H), 0.98-1.28 (m, 4H), 1.54-1.78 (m, 8H), 2.24 (m,2H), 2.39 (m, 1H), 2.53 (m, 1H), 3.29 (m, 3H), 6.41 (q, 1H). MS (ESI)rn/z 462.06 (M+Na)⁺.

Example 73: Asymmetric Synthesis of Sodium4-{[(1S)-Butanoyloxybutoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoate(86) Step A: Synthesis of[(1S)-Butanoylbutoxy]-(4-nitrophenyl)-carbonate (87)

To a solution of (5S)-5-hydroxyoctan-4-one (1.10 g, 7.63 mmol) in CH₂Cl₂(50 mL) at 0° C. was added p-nitrophenyl chloroformate (1.90 g, 9.14mmol), pyridine (0.98 mL, 12.1 mmol) and 4-dimethylaminopyridine (186mg, 1.52 mmol). The resulting mixture was stirred at 0° C. for 1 h thenat room temperature overnight. The reaction mixture was diluted inCH₂Cl₂, washed excessively with water, dilute HCl and brine, and driedover anhydrous Na₂SO₄. Filtration and removal of the solvent in vacuoafforded the crude carbonate, which was purified by chromatography onsilica gel, eluting with 5% ether in hexane to afford the title compound(87) (1.45 g, 65%). ¹H NMR (CDCl₃, 400 MHz): δ 0.94 (t, 3H) 0.99 (t,311), 1.51 (hex, 2H), 1.66 (hex, 2H), 1.85 (m, 2H), 2.48 (m, 2H), 5.03(AB q, 1H), 7.03 (d, 2H), 8.26 (d, 2H).

Step B: Synthesis of4-{[(1S)-Butanoylbutoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoicAcid (88)

To a stirred suspension of R-baclofen (1.0 g, 4.69 mmol) in CH₂Cl₂ (50mL) at 0° C. was added triethylamine (2.4 mL, 18.76 mmol) and TMSCl(1.19 mL, 9.38 mmol). The resulting reaction mixture was stirred at 0°C. for 15 min. Then, to the suspension was added a solution of compound(87) (4.7 mmol) in CH₂Cl₂ (5 mL) and the resulting reaction mixturestirred at room temperature for 5 h. The mixture was diluted withCH₂Cl₂, washed with ice-cold dilute HCl and brine, and dried overanhydrous Na₂SO₄. The solvent was removed in vacuo to afford the crudeproduct, which was purified by chromatography on silica gel, elutingfirst with pure CH₂Cl₂ to remove p-nitrophenol, and then with 20% ethylacetate in CH₂Cl₂ to afford the carbamate compound (88) (1.20 g, 67%).¹H NMR (CDCl₃, 400 MHz): δ 0.90 (m, 6H), 1.33 (m, 2H), 1.60 (m, 4H),2.39 (m, 2H), 2.58 (m, 1H), 2.71 (m, 1H), 3.3.25-3.50 (m, 3H), 4.90 (ABq, 1H), 5.06 (t, 1H), 7.13 (d, 2H), 7.26 (d, 2H).

Step C:4-{[(1S)-Butanoyloxybutoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoicAcid (89)

To a stirred suspension of urea-hydrogen peroxide (1.43 g, 15.2 mmol) inCH₂Cl₂ (30 mL) at 0° C. was added carbamate (88) (417 mg, 1.09 mmol) inCH₂Cl₂ (5 mL), followed by dropwise addition of trifluoroaceticanhydride (1.06 mL, 7.60 mmol). The resulting reaction mixture wasstirred at 0° C. and quenched after 5 h. The reaction mixture was washedwith water and brine, then dried over anhydrous Na₂SO₄ to afford thecrude product, which was purified by preparative LC/MS to afford thetitle compound (89) (189 mg, 43.5%) as a single diastereomer (asdetermined by chiral LC/MS). ¹H NMR (CDCl₃, 400 MHz): δ 0.92 (m, 6H),1.38 (m, 2H), 1.65 (m, 4H), 2.28 (t, 2H), 2.59 (dd, 1H), 2.70 (dd, 1H),3.29 (m, 2H), 3.50 (m, 1H), 4.78 (br. m, 1H), 6.67 (t, 1H), 7.11 (d,2H), 7.26 (d, 2H). MS (ESI) m/z 398.14 (M−H)⁻.

Step D: Sodium4-{[(1S)-Butanoyloxybutoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoate(86)

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (86).

Example 74: Asymmetric Synthesis of Sodium4-{[(1R)-Butanoyloxyisobutoxyl]carbonylamino}-(3R)-(4-chlorophenyl)-butanoate(90)

Following the procedures of Example 73 but replacing(5S)-5-hydroxyoctan-4-one with (3R)-3-hydroxy-2-methylheptan-4-one, thefree acid form of the title compound was obtained as a singlediastereomer (158 mg, 23%). ¹H NMR (CDCl₃, 400 MHz): δ 0.91 (m, 9H) 1.63(hept, 2H), 1.94 (m, 2H), 2.29 (t, 2H), 2.60 (dd, 1H), 2.71 (dd, 1H),3.30 (m, 2H), 3.51 (m, 1H), 4.70 (t, 1H), 6.51 (d, 1H), 7.12 (d, 2H),7.26 (d, 2H). MS (ESI) m/z 398.14 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (90).

Example 75: Asymmetric Synthesis of Sodium4-{[(1S)-Isobutanoyloxybutoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoate(91)

Following the procedures of Example 73 but replacing(5S)-5-hydroxyoctan-4-one with (4S)-4-hydroxy-2-methylheptan-3-one, thefree acid form of the title compound was obtained as a singlediastereomer (20 mg, 7%). ¹H NMR (CDCl₃, 400 MHz): δ 0.93 (t, 3H), 1.16(m, 6H), 1.34 (m, 2H), 1.68 (m, 2H), 2.52 (m, 1H), 2.58 (dd, 1H), 2.71(dd, 1H), 3.30 (m, 2H), 3.52 (m, 1H), 4.70 (t, 1H), 6.67 (t, 1H), 7.12(d, 2H), 7.26 (d, 2H). MS (ESI) m/z 398.14 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (91).

Example 76: Asymmetric Synthesis of Sodium4-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoate(92)

Following the procedures of Example 73 but replacing(5S)-5-hydroxyoctan-4-one with (4S)-2,5-dimethyl-4-hydroxyhexan-3-one,the free acid form of the title compound was obtained as a singlediastereomer (8.0 mg, 2%). ¹H NMR (CDCl₃, 400 MHz): δ 0.89 (m, 6H), 1.15(m, 6H), 1.94 (m, 1H), 2.52 (m, 1H), 2.58 (dd, 1H), 2.78 (dd, 1H), 3.28(m, 2H), 3.49 (m, 1H), 4.68 (t, 1H), 6.48 (d, 1H), 7.10 (d, 2H), 7.24(d, 2H). MS (ESI) m/z 398.14 (M−H)⁻.

The carboxylic acid was converted to the sodium salt by dissolution inMeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 10 min. The solvent was removed by lyophilization toafford the title compound (92).

Example 77: Synthesis of O-(1-Isobutanoyloxyisobutoxy) S-MethylThiocarbonate (93) Step A: O-(1-Chloroisobutoxy) S-Methyl Thiocarbonate(94)

A solution of 1-chloro-2-methylpropyl chloroformate (1026 g, 6.0 mol)and tetrabutylammonium hydrogensulfate (20 g, 60 mmol) indichloromethane (1500 mL) in a jacketed 10 L reactor equipped with amechanical stirrer, temperature probe, and addition funnel was cooled to10° C. To the reaction mixture was gradually added a 15% aqueoussolution of sodium methylthiolate (3 L, 6.4 mol) over 4 h. The reactionwas moderately exothermic and the internal temperature was maintainedbetween 10 and 20° C. during the addition. The aqueous phase wasseparated and the organic phase was washed with brine (2×2 L) and water(2 L). The organic layer was dried over anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure to afford the title compound (94)(1050 g, 5.76 mol, 96%) as a colorless liquid. ¹H NMR (CDCl₃, 400 MHz):δ 1.1 (dd, 6H), 2.2 (m, 1H), 2.4 (s, 3H), 6.35 (d, 1H).

Step B: Tetramethylammonium Isobutyrate (95)

To a 20 L round bottom flask was added isobutyric acid (1300 mL, 14mol), and an aqueous solution of 25% tetramethylammonium hydroxide (5 L,14 mol). The water was removed under reduced pressure, and azeotropedwith toluene (2×2 L) to leave the product (95) as an amber liquid, whichwas used without further purification.

Step C: O-(1-Isobutanoyloxyisobutoxy) S-Methyl Thiocarbonate (93)

To a 3 L three neck round bottom flask equipped with a mechanicalstirrer and teflon-coated thermocouple was added (95) (1672 g, 9 mol),isobutyric acid (264 g, 1.5 mol), and (94) (1050 g, 5.76 mol). Thereaction mixture was heated to 80° C. for 12 h, monitoring the reactionprogress by ¹H NMR. The reaction mixture was cooled to 20° C., dilutedwith EtOAc (1 L) and washed with water (2×1 L), saturated NaHCO₃ (1×2 L)and water (1 L). The organic phase was separated and concentrated underreduced pressure to afford the product (93) (905 g, 3.9 mol, 65%) as acolorless liquid. ¹H NMR (CDCl₃, 400 MHz): δ 1.0 (d, 6H), 1.2 (dd, 6H),2.05 (m, 1H), 2.35 (s, 3H), 2.6 (m, 1H), 6.7 (d, 1H).

Example 78: Synthesis of(1R)-1-[((3S,4S)-2,5-Dioxo-3,4-dibenzoyloxypyrrolidinyl)-oxycarbonyloxy]-2-methylpropyl2-methylpropanoate (96)

Step A: (3S,4S)-2,5-Dioxo-3,4-dibenzoyloxy-3,4-dihydrofuran (97) Asuspension of 2,3-dibenzoyl-D-tartaric acid (100 g, 279 mmol) in aceticanhydride (300 mL) was stirred at 85° C. for 2 h then the reactionmixture allowed to cool to room temperature. The crystalline product wascollected by filtration, washed with a mixture of ether and hexane (1:1)and dried under vacuum to afford the title compound (97) (80 g, 84%). ¹HNMR (CDCl₃, 400 MHz): δ 5.99 (s, 2H), 7.50 (m, 4H), 7.66 (m, 2H), 8.07(m, 4H).

Step B: 1-Hydroxy-(3S,4S)-2,5-Dioxo-3,4-dibenzoyloxypyrrolidine (98)

To a suspension of (97) (60 g, 176 mmol) in a mixture of acetonitrileand water (8:1, 400 mL) at 0° C. was added a 50% aqueous solution ofhydroxylamine (13.0 mL, 211 mmol). The resulting suspension was stirredovernight at room temperature to obtain a clear solution. The bulk ofthe acetonitrile was removed by rotary evaporation and the residue wasportioned between ethyl acetate and water. The organic phase was washedsuccessively with water and brine, dried over anhydrous Na₂SO₄ andconcentrated in vacuo to afford the intermediate, 2,3-dibenzoyloxyD-tartaric acid mono-hydroxamate. This compound was suspended in tolueneheated under reflux for 2 h, then cooled to room temperature to form acrystalline solid. The product was collected by filtration, washed witha mixture of ether and hexane (1:1), and dried under vacuum to affordthe title compound (98) (58 g, 93%). ¹H NMR (CDCl₃, 400 MHz): δ 6.06 (s,2H), 7.50 (t, 4H), 7.65 (dt, 2H), 8.06 (m, 4H). MS (ESI) m/z 354.00(M−H)⁻.

Step C:(1R)-1-[((3S,4S)-2,5-Dioxo-3,4-dibenzoyloxypyrrolidinyl)-oxycarbonyloxy]-2-methylpropyl2-methylpropanoate (96)

To a stirred solution of compound (98) (35 g, 98.6 mmol) andthiocarbonate (93) (34.6 g, 148 mmol) in dichloromethane at 0° C. wasdropwise added a 32% solution of peracetic acid (300 mmol) in aceticacid over 2 h. The reaction temperature was kept below 35° C. during theaddition of peracetic acid. After the addition was complete, thereaction mixture was stirred overnight at room temperature. Theresulting white precipitate was filtered and washed successively withwater, and a mixture of ether and hexane (1:2), then dried under vacuumto afford the crude title compound. This product was crystallized oncefrom a mixture of ethyl acetate and hexane (1:1) to afford the titlecompound (96) (13.7 g, 25%). The diastereomeric purity of the productwas determined to be 98.4% d.e. by HPLC using a chiral column. ¹H NMR(CDCl₃, 400 MHz): δ 1.06 (d, 6H), 1.22 (d, 3H), 1.22 (d, 3H), 2.20 (m,1H), 2.64 (hept. 1H), 6.01 (br. s, 2H), 6.64 (d, 1H), 7.47 (m, 4H), 7.63(m, 2H), 8.07 (m, 4H).

Example 79: Synthesis of4-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoicAcid (99)

To a stirred suspension of (96) (11.7 g, 21.7 mmol) in a mixture of THFand water (10:1) (220 mL) at room temperature was added R-baclofen (4.78g, 22.5 mmol). The resulting reaction mixture was stirred until thesuspension became a clear solution (ca. 2 h) then was concentrated invacuo to remove most of the solvent. The residue was partitioned betweenether and water, the ether layer was washed with water and brine, anddried over anhydrous Na₂SO₄. After filtration and concentration invacuo, the crude product was obtained and then purified byflash-chromatography on silica gel, eluting with a gradient of 10-20%acetone in hexane. Crystallization from an acetone/hexane mixtureafforded the title compound (99) (8.22 g, 95% yield). The diastereomericpurity of the product was determined to be 99.9% d.e. by HPLC using achiral column. ¹H NMR (CDCl₃, 400 MHz): δ 0.95 (d, 6H), 1.17 (d, 3H),1.18 (d, 3H), 1.99 (m, 1H), 2.55 (hept. 1H), 2.64 (dd, 1H), 2.76 (dd,1H), 3.40 (m, 3H), 4.73 (br. t, 1H), 6.51 (d, 1H), 7.13 (d, 2H), 7.27(m, 2H). MS (ESI) m/z 398.50 (M−H)⁻.

Example 80: Synthesis of Sodium4-{[(1R)-Isobutanoyloxyisobutoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoate(100)

The carboxylic acid (99) was converted to the sodium salt by dissolutionin MeCN (0.5 mL) and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 15 min. The solvent was removed by lyophilization toafford the title compound (100). ¹H NMR (CD₃OD, 400 MHz): δ 0.93 (d,3H), 0.94 (d, 3H), 1.08 (d, 3H), 1.10 (d, 3H), 1.94 (m, 1H), 2.37-2.54(m, 3H), 3.31 (m, 3H), 6.43 (d, 1H), 7.23 (s, 4H). MS (ESI) m/z 398.57(M-Na)⁻.

Example 81: Synthesis of(1S)-1-[((3R,4R)-2,5-Dioxo-3,4-dibenzoyloxypyrrolidinyl)-oxycarbonyloxy]-2-methylpropyl2-methylpropanoate (101) Step A:(3R,4R)-2,5-Dioxo-3,4-dibenzoyloxy-3,4-dihydrofuran (102)

To a 3-necked 5 L round bottom flask fitted with a mechanical stirrerand a teflon coated thermocouple was added (−)-2,3-dibenzoyl-L-tartaricacid (1000 g, 2.79 mol) followed by acetic anhydride (2 L). Thesuspension was stirred and heated to 85° C. for 2 h during which timethe starting material gradually dissolved. A short time thereafter, theproduct began to crystallize in the reaction mixture and the suspensionwas then cooled to 25° C. The product was collected by filtration,washed with 10% acetone in hexane (2×1 L), and dried in a vacuum oven at50° C. overnight to afford the title compound (102) as a white solid. ¹HNMR (CDCl₃, 400 MHz): δ 6.0 (s, 2H), 7.45 (app. t, 4H), 7.65 (app. t,2H), 8.05 (d, 4H).

Step B: 1-Hydroxy-(3R,4R)-2,5-Dioxo-3,4-dibenzoyloxypyrrolidine (103)

To a 3-neck 5 L round bottom flask fitted with a mechanical stirrer anda teflon coated temperature probe was added (102) (2.79 mol) followed byacetonitrile (2 L). The suspension was cooled in an ice bath to 4° C.,followed by the addition of 50% aqueous hydroxylamine (180 mL, 2.93 mol)over 1 h. The starting material gradually dissolved during the additionand the reaction mixture was warmed to 20° C. and stirred for 1 h. Thereaction mixture was concentrated in vacuo, diluted with EtOAc (1 L) andwashed with 1 N HCl (2×1 L). The organic phase was separated andconcentrated in vacuo to afford a viscous red syrup. The syrup was thenheated for two hours in toluene (2.5 L) at 100° C. with azeotropicremoval of water. The syrup gradually dissolved and then the productcrystallized. After cooling to room temperature the solid was collectedby filtration, washed with 10% acetone in hexane (2×1 L) and dried in avacuum oven to afford the title compound (103) (862 g, 2.43 mol, 87%) asa white solid. ¹H NMR (CDCl₃, 400 MHz): δ 5.85 (s, 2H), 7.45 (app. t,4H), 7.65 (app t, 2H), 8.05 (m, 4H).

Step C:(1S)-1-[((3R,4R)-2,5-Dioxo-3,4-dibenzoyloxypyrrolidinyl)-oxycarbonyloxy]-2-methylpropyl2-methylpropanoate (101)

A 3 L three necked round bottom flask fitted with a mechanical stirrer,teflon coated temperature probe and an addition funnel was charged with(93) (234 g, 1 mol), (103) (330 g, 0.95 mol), and 1,2-dichloroethane(2200 mL). The reaction mixture was cooled under a nitrogen atmospherein an ice water bath to 15° C. To the stirred reaction mixture was addeda 39% solution of peracetic acid in dilute acetic acid (500 mL, 2.94mol) over 2 h, maintaining the temperature between 15 and 22° C. Thistemperature was maintained for an additional 12 h during which time awhite precipitate was formed. The reaction mixture was further cooled to3-4° C., the product collected by filtration, and washed with hexane(2×1 L). The product was dried in vacuo, yielding the title compound(101) (128 g, 0.24 mol, 25%). The diastereomeric purity of the productwas determined to be >99% d.e. by HPLC using a chiral column. ¹H NMR(CDCl₃, 400 MHz): δ 1.0 (d, 6H), 1.2 (dd, 6H), 2.1 (m, 1H), 2.65 (m,1H), 6.0 (br. s, 2H), 6.6 (d, 1H), 7.45 (app. t, 4H), 7.65 (app. t, 2H),8.05 (d, 4H).

Example 82: Synthesis of4-{[(1S)-Isobutanoyloxyisobutoxy]carbonylamino}-(3R)-(4-chlorophenyl)-butanoicAcid (104)

To a 3 L three necked round bottom flask fitted with a mechanicalstirrer, temperature probe, and nitrogen inlet was added (101) (75 g,139 mmol), R-baclofen (31.2 g, 146 mmol), THF (1000 mL), and water (100mL). The suspension was stirred under a nitrogen atmosphere at 18-20° C.for 4 h. The reaction became homogenous in 30 min. The THF was removedin vacuo and the reaction mixture was diluted with methyl tert-butylether (250 mL) and washed with 1N HCl (1×500 mL) and water (2×200 mL).The organic phase was separated and concentrated in vacuo to leave awhite solid. The solid was purified by flash chromatography (800 gsilica gel; eluting with 20% acetone in hexane) to afford the product(50 g, 125 mmol, 90% yield) as a white solid. Crystallization fromeither an acetone/hexane mixture or ethyl acetate/heptane mixtureafforded the title compound (104) (50 g, 125 mmol, 90% yield) as a whitesolid. The diastereomeric purity of the product was determined tobe >99% d.e. by HPLC using a chiral column. ¹H NMR (CDCl₃, 400 MHz): δ0.89 (m, 6H), 1.15 (m, 6H), 1.94 (m, 1H), 2.52 (m, 1H), 2.58 (dd, 1H),2.78 (dd, 1H), 3.28 (m, 2H), 3.49 (m, 1H), 4.68 (t, 1H), 6.48 (d, 1H),7.10 (d, 2H), 7.24 (d, 2H). MS (ESI) m/z 398.14 (M−H)⁻.

Example 83: Synthesis of Sodium4-{[(1S)-Isobutanoyloxyisobutoxyl]carbonylamino}-(3R)-(4-chlorophenyl)-butanoate(92)

The carboxylic acid (101) was converted to the sodium salt bydissolution in MeCN and then addition of aqueous NaHCO₃ (1 eq.) withsonication for 15 min. The solvent was removed by lyophilization.Crystallization from either mixtures of acetone/hexane, ethylacetate/heptane, THF/heptane or 1,2-dimethoxyethane/hexane afforded thetitle compound (92) as a white crystalline solid. 1H NMR (CD₃OD, 400MHz): δ 0.90 (d, 6H), 1.14 (d, 3H), 1.15 (d, 3H), 1.91 (m, 1H), 2.40 (m,1H), 2.52 (m, 2H), 3.30 (m, 3H), 6.41 (d, 1H), 7.22 (s, 4H). MS (ESI)m/z 398.08 (M-Na)⁻.

Example 84: Standard Methods for Determination of Enzymatic Cleavage ofProdrugs in Vitro

The stabilities of prodrugs were evaluated in one or more in vitrosystems using a variety of tissue preparations following methods knownin the art. The chemical stability of prodrugs in aqueous buffers atpH's of 2.0, 7.4 and 8.0 were also measured. Tissues were obtained fromcommercial sources (e.g., Pel-Freez Biologicals, Rogers, Ark., orGenTest Corporation, Woburn, Mass.). Experimental conditions used forthe in vitro studies are described in Table 1 below. Each preparationwas incubated with test compound at 37° C. for one hour. Aliquots (50μL) were removed at 0, 30, and 60 min and quenched with 0.1%trifluoroacetic acid in acetonitrile. Samples were then centrifuged andanalyzed by LC/MS/MS (see Example 86 below for method details).Stability of prodrugs towards specific enzymes (e.g., peptidases, etc.)were also assessed in vitro by incubation with the purified enzyme:

Pancreatin Stability:

Stability studies were conducted by incubating prodrug (5 μM) with 1%(w/v) pancreatin (Sigma, P-1625, from porcine pancreas) in 0.025 M Trisbuffer containing 0.5 M NaCl (pH 7.5) at 37° C. for 60 min. The reactionwas stopped by addition of 2 volumes of methanol. After centrifugationat 14,000 rpm for 10 min, the supernatant was removed and analyzed byLC/MS/MS.

Caco-2 Homogenate S9 Stability:

Caco-2 cells were grown for 21 days prior to harvesting. Culture mediumwas removed and cell monolayers were rinsed and scraped off intoice-cold 10 mM sodium phosphate/0.15 M potassium chloride, pH 7.4. Cellswere lysed by sonication at 4° C. using a probe sonicator. Lysed cellswere then transferred into 1.5 mL centrifuge vials and centrifuged at9000 g for 20 min at 4° C. The resulting supernatant (Caco-2 cellhomogenate S9 fraction) was aliquoted into 0.5 mL vials and stored at−80° C. until used.

For stability studies, prodrug (5 μM) was incubated in Caco-2 homogenateS9 fraction (0.5 mg protein per mL) for 60 min at 37° C. Concentrationsof intact prodrug and released baclofen were determined at zero time and60 minutes using LC/MS/MS. Data from these studies is summarized inTable 2.

TABLE 1 Standard Conditions for Prodrug In Vitro Metabolism StudiesSubstrate Preparation Concentration Cofactors Rat Plasma 2.0 μM NoneHuman Plasma 2.0 μM None Rat Liver S9 2.0 μM NADPH* (0.5 mg/mL) HumanLiver S9 2.0 μM NADPH* (0.5 mg/mL) Human Intestine 2.0 μM NADPH* S9 (0.5mg/mL) Carboxypeptidase A 2.0 μM None (10 units/mL) Caco-2 5.0 μM NoneHomogenate Pancreatin 5.0 μM None *NADPH generating system, e.g., 1.3 mMNADP+, 3.3 mM glucose-6-phosphate, 0.4 U/mL glucose-6-phosphatedehydrogenase, 3.3 mM magnesium chloride and 0.95 mg/mL potassiumphosphate, pH 7.4.

TABLE 2 % of Prodrug Remaining/% of Baclofen Released from BaclofenProdrugs after 60 min. in Various Tissue Preparations (10) (12) (14)(16) (18) (20) (23) pH 2.0 100/1  100/0  100/1  100/0  105/0  100/0107/0  pH 7.4 101/3  100/0  103/1  100/0  95/0  100/0 89/1  pH 8.0 98/9 105/0  102/2  100/0  102/0  103/0 90/2  Rat Plasma 85/15 72/14 55/4854/40 39/60  92/8 11/93 Human Plasma 64/26 95/5  90/10 62/20 61/27  82/996/3  Rat Liver S9  0/78  3/100  2/99  1/100  1/100  25/75  3/107 (0.5mg/mL) Human Liver S9  1/80  1/100  2/102  1/100  2/100   1/100  4/105(0.5 mg/mL) Caco-2 S9  2/96  2/100  2/97  1/100  1/100   1/100 15/87Pancreatin 75/21 15/77  2/101  1/84  2/91  58/36 82/24 (25) (27) (30)(33) (34) (40) (43) pH 2.0 101/0  102/0  100/0  100/0  100/0  103/0 95/0  pH 7.4 100/0  100/0  87/1  72/0  100/0  100/0  87/0  pH 8.0 100/0 101/1  81/3  101/0  100/0  107/2  92/0  Rat Plasma  5/96 12/88 58/4273/30 78/18 72/17 71/29 Human Plasma 93/4  82/12 85/8  96/4  90/2 101/2  100/2  Rat Liver S9  1/98  0/89  1/85  4/101  1/100  8/96  3/97(0.5 mg/mL) Human Liver S9  4/91  8/79  7/87  3/101  3/100  1/105 61/39(0.5 mg/mL) Caco-2 S9  2/95 27/67 24/70  3/95  2/100 15/85 51/49Pancreatin 22/84 71/9  90/9  46/52 81/18 43/58 82/4  (51) (57) (59) (62)(84) (85) (86) pH 2.0 100/0  100/0  103/0  105/0  85/0  82/0  101/0   pH7.4 97/2  100/0  103/1  94/2  84/0  92/0  99/1  pH 8.0 91/9  100/0 97/2  88/8  94/1  93/0  94/2  Rat Plasma 31/72 82/10  2/85  5/95 91/1182/12 1/83 Human Plasma 53/50 73/14 77/11 84/2  89/4  95/4  73/13  RatLiver S9  2/103  2/78  2/85  2/80  4/91  2/91 2/92 (0.5 mg/mL) HumanLiver S9  6/91  1/86  1/82  0/69  2/82  2/84 2/87 (0.5 mg/mL) Caco-2 S9 3/100  2/104  3/104  1/89 13/76  4/82 2/95 Pancreatin 44/50 12/75 46/50 1/79 47/40 15/64 4/76 (90) (91) (92) (100) (104) pH 2.0 97/0  100/0 97/0  101/0  100/0  pH 7.4 93/0  97/0  95/0  98/0  100/0  pH 8.0 93/1 94/1  96/1  95/0  100/0  Rat Plasma  5/77 80/10 12/73  9/64 14/85 HumanPlasma 81/2  83/2  86/1  89/3  98/2  Rat Liver S9  3/85 22/70  6/88 3/85  3/97 (0.5 mg/mL) Human Liver S9  1/78  1/78  4/80  1/83  3/97(0.5 mg/mL) Caco-2 S9  5/90  6/107 55/53  7/90 17/83 Pancreatin  9/6811/78 85/7  68/27 90/6 

Example 85: In Vitro Determination of Caco-2 Cellular Permeability ofProdrugs

The trans-epithelial cellular permeability of prodrugs of baclofen andbaclofen analogs may be assessed in vitro using standard methods wellknown in the art (see, e.g., Stewart, et al., Pharm. Res., 1995, 12,693). For example, cellular permeability may be evaluated by examiningthe flux of a prodrug across a cultured polarized cell monolayer (e.g.,Caco-2 cells). Caco-2 cells obtained from continuous culture (passageless than 28) were seeded at high density onto Transwell polycarbonatefilters. Cells were maintained with DMEM/10% fetal calf serum +0.1 mMnonessential amino acids+2 mM L-Gln, 5% CO₂/95% O₂, 37° C. until the dayof the experiment. Permeability studies were conducted at pH 6.5apically (in 50 mM MES buffer containing 1 mM CaCl₂, 1 mM MgCl₂, 150 mMNaCl, 3 mM KCl, 1 mM NaH₂PO4, 5 mM glucose) and pH 7.4 basolaterally (inHanks' balanced salt solution containing 10 mM HEPES) in the presence ofefflux pump inhibitors (250 μM MK-571, 250 μM Verapamil, 1 mMOfloxacin). Inserts were placed in 12 or 24 well plates containingbuffer and incubated for 30 min at 37 C.°. Prodrug (200 μM) was added tothe apical or basolateral compartment (donor) and concentrations ofprodrug and/or released parent drug in the opposite compartment(receiver) were determined at intervals over 1 hour using LC/MS/MS.Values of apparent permeability (P_(app)) were calculated using theequation:

P _(app) =V _(r)(dC/dt)//(AC _(o))

Here V_(r) is the volume of the receiver compartment in mL; dC/dt is thetotal flux of prodrug and parent drug (μM/s), determined from the slopeof the plot of concentration in the receiver compartment versus time;C_(o) is the initial concentration of prodrug in μM; A is the surfacearea of the membrane in cm². Preferably, prodrugs with significanttranscellular permeability demonstrate a value of P_(app) of ≧1×10⁻⁶cm/s and more preferably, a value of P_(app) of ≧1×10⁻⁵ cm/s, and stillmore preferably a value of P_(app) of ≧5×10⁻⁵ cm/s. Typical values ofP_(app) obtained for baclofen prodrugs are shown in the following table:

P_(app) (apical to P_(app) (basolateral to Ratio Compound basolateral)(cm/s) apical) (cm/s) A-B/B-A (10) 1.1 × 10⁻⁶ 9.2 × 10⁻⁷ 1.2 (12) 1.0 ×10⁻⁴ 1.7 × 10⁻⁵ 5.9 (14) 2.2 × 10⁻⁵ 5.3 × 10⁻⁶ 4.1 (16) 6.1 × 10⁻⁶ 1.2 ×10⁻⁶ 5.1 (18) 6.4 × 10⁻⁶ 5.6 × 10⁻⁶ 1.1 (20) 9.1 × 10⁻⁵ 7.7 × 10⁻⁶ 11.8(25) 5.8 × 10⁻⁵ 1.4 × 10⁻⁵ 4.1 (27) 6.5 × 10⁻⁵ 9.4 × 10⁻⁶ 6.9 (30) 8.7 ×10⁻⁶ 2.3 × 10⁻⁶ 3.8 (32) 3.7 × 10⁻⁵ 4.9 × 10⁻⁶ 7.6 (36) 2.9 × 10⁻⁵ 1.9 ×10⁻⁵ 1.5 (38) 1.5 × 10⁻⁵ 1.4 × 10⁻⁵ 1.1 (40) 6.9 × 10⁻⁵ 3.0 × 10⁻⁵ 2.3(43) 4.2 × 10⁻⁵ 1.8 × 10⁻⁵ 2.3 (48) 1.1 × 10⁻⁵ 1.7 × 10⁻⁶ 6.5 (50) 2.5 ×10⁻⁵ 1.4 × 10⁻⁵ 1.8 (51) 2.9 × 10⁻⁵ 9.6 × 10⁻⁶ 3.0 (53) 8.5 × 10⁻⁵ 3.6 ×10⁻⁵ 2.4 (71) 9.2 × 10⁻⁵ 1.3 × 10⁻⁵ 7.1 (72) 2.8 × 10⁻⁵ 8.0 × 10⁻⁶ 3.5(73) 2.2 × 10⁻⁵ 6.8 × 10⁻⁶ 3.2 (74) 1.0 × 10⁻⁵ 8.9 × 10⁻⁷ 11.2 (78) 1.5× 10⁻⁵ 1.9 × 10⁻⁶ 7.9

The data in this table shows that several of the prodrugs disclosedherein have high cellular permeability and should be well absorbed fromthe intestine. With the exception of compound (10), theapical-to-basolateral permeabilities of these prodrugs significantlyexceed their basolateral-to-apical permeabilities, suggesting that thesecompounds may be substrates for active transport mechanisms present inthe apical membrane of Caco cells (though some component of thistranscellular permeability may also be mediated by passive diffusion).

Example 86: Uptake of R-Baclofen Following Administration of R-Baclofenor R-Baclofen Prodrugs Intracolonically in Rats

Sustained release oral dosage forms, which release drug slowly overperiods of 6-24 hours, generally release a significant proportion of thedose within the colon. Thus, drugs suitable for use in such dosage formspreferably exhibit good colonic absorption. This experiment wasconducted to assess the suitability of baclofen prodrugs for use in anoral sustained release dosage form.

Step A: Administration Protocol

Rats were obtained commercially and were pre-cannulated in the both theascending colon and the jugular vein. Animals were conscious at the timeof the experiment. All animals were fasted overnight and until 4 hourspost-dosing. R-Baclofen or baclofen prodrugs (10), (12), (23), (25),(27), (32), (33), (40), (51), (92), (100) and (104) were administered asa solution (in water or PEG 400) directly into the colon via the cannulaat a dose equivalent to 10 mg of baclofen equivalents per kg bodyweight. Blood samples (0.5 mL) were obtained from the jugular cannula atintervals over 8 hours and were quenched immediately by addition ofmethanol to prevent further conversion of the prodrug. Blood sampleswere analyzed as described below.

Step B: Sample preparation for colonic absorbed drug

-   -   1. Rat blood was collected at different time points and 100 μL        of blood was added into an eppendorf tube containing 300 μL of        methanol and vortexed to mix immediately.    -   2. 20 μL of p-chlorophenylalanine was added as an internal        standard.    -   3. 300 μL of methanol was added into each tube followed by 20 μL        of p-chlorophenylalanine. 90 μL of blank rat blood was added to        each tube and mix. Then 10 μL of a baclofen standard solution        (0.04, 0.2, 1, 5, 25, 100 μg/mL) was added to make up a final        calibration standard (0.004, 0.02, 0.1, 0.5, 2.5, 10 pg/mL).    -   4. Samples were vortexed and centrifuged at 14,000 rpm for 10        min.    -   5. Supernatant was taken for LC/MS/MS analysis.

Step C: LC/NIS/MS Analysis

An API 2000 LC/MS/MS spectrometer equipped with Shidmadzu 10ADVp binarypumps and a CTC HTS-PAL autosampler were used in the analysis. APhenomenex hydro-RP 4.6×50 mm column was used during the analysis. Themobile phase was water with 0.1% formic acid (A) and acetonitrile with0.1% formic acid (B). The gradient condition was: 10% B for 0.5 min,then to 95% B in 2.5 min, then maintained at 95% B for 1.5 min. Themobile phase was returned to 10% B for 2 min. A TurbolonSpray source wasused on the API 2000. The analysis was done in positive ion mode and anMRM transition of m/z 214/151 was used in the analysis of baclofen (MRMtransitions m/z 330/240 for (10), m/z 392/240 for (12), m/z 372/240 for(23), m/z 400/240 for (25), m/z 400/240 for (27), m/z 372/240 for (32),m/z 372/240 for (33), 406/240 for (40), 454/61 for (51), 400/240 for(92), 400/240 for (100) and 400/240 for (104) were used). 10 μL of thesamples were injected. The peaks were integrated using Analyst 1.2quantitation software. Following colonic administration of prodrugs(12), (23), (25), (27), (32), (33), (40), (51), (92), (100) and (104)the maximum plasma concentrations of R-baclofen (C_(max)), as well asthe area under the baclofen plasma concentration vs. time curves (AUC)were significantly greater (>2-fold) than that produced from colonicadministration of R-baclofen itself. This data demonstrates that thesecompounds may be formulated as compositions suitable for enhancedabsorption and/or effective sustained release of baclofen analogs tominimize dosing frequency due to rapid systemic clearance of thesebaclofen analogs.

Example 87: Pharmacokinetics of R-Baclofen Following IntravenousAdministration to Cynomolgus Monkeys

R-Baclofen hydrochloride salt was administered to four male cynomolgusmonkeys as an aqueous solution by intravenous bolus injection into thesaphenous vein at a dose of 1.2 mg/kg. Blood samples were obtained fromall animals at intervals over 24 hours post-dosing. Blood was processedimmediately for plasma at 4° C. All plasma samples were subsequentlyanalyzed for R-baclofen using the LC/MS/MS assay described above. Themean R-baclofen exposure AUC_(inf)=3.6 h.μg/mL.

Example 88: Uptake of R-Baclofen Following Administration of R-Baclofenor R-Baclofen Prodrugs Intracolonically in Cynomolgus Monkeys

R-Baclofen hydrochloride salt and R-baclofen prodrugs (5 mgbaclofen-eq/kg) were administered to groups of four male cynomolgusmonkeys as either aqueous solutions or suspensions in 0.5% methylcellulose/0.1% Tween-80 via bolus injection directly into the colon viaan indwelling cannula. For colonic delivery a flexible French catheterwas inserted into the rectum of each monkey and extended to the proximalcolon (approx. 16 inches) using fluoroscopy. Monkeys were lightlysedated by administration of Telazol/ketamine during dosing. A washoutperiod of at least 5 to 7 days was allowed between treatments. Followingdosing, blood samples were obtained at intervals over 24 hours and wereimmediately quenched and processed for plasma at 4° C. All plasmasamples were subsequently analyzed for R-baclofen and intact prodrugusing the LC/MS/MS assay described above. Following colonicadministration of prodrugs (12), (22), (25), (40) and (51), the maximumplasma concentrations of baclofen (C_(max)), as well as the area underthe baclofen plasma concentration vs. time curves (AUC) weresignificantly greater (>2-fold) than that produced from colonicadministration of R-baclofen itself, while colonic administration of(92), (100) and (104) produced R-baclofen exposures that were greaterthan 10-fold that produced from colonic administration of R-baclofenitself. This data demonstrates that these compounds may be formulated ascompositions suitable for enhanced absorption and/or effective sustainedrelease of baclofen analogs to minimize dosing frequency due to rapidsystemic clearance of these baclofen analogs.

Example 89: Uptake of R-Baclofen Following Oral Administration ofR-Baclofen Prodrugs to Cynomolgus Monkeys

The R-baclofen prodrugs (92) and (104) (5 mg baclofen-eq/kg) wereadministered by oral gavage to groups of four male cynomolgus monkeys aseither an aqueous solution or suspension in 0.5% methyl cellulose/0.1%Tween-80 respectively. Following dosing, blood samples were obtained atintervals over 24 hours and were immediately quenched and processed forplasma at 4° C. All plasma samples were subsequently analyzed forR-baclofen and intact prodrug using the LC/MS/MS assay described above.The oral bioavailability of both prodrugs (92) and (104) as R-baclofenwas determined to be greater than 80%.

Finally, it should be noted that there are alternative ways ofimplementing thedisclosures contained herein. Accordingly, the presentembodiments are to be considered as illustrative and not restrictive,and the claims are not to be limited to the details given herein, butmay be modified within the scope and equivalents thereof. Allpublications and patents disclosed herein are incorporated herein byreference in their entirety.

1-52. (canceled)
 53. A method of synthesizing a compound of Formula (I)comprising contacting a compound of Formula (II) with a compound ofFormula (III):

in the presence of a member of the group selected from an organic base,an inorganic base, and a metal salt, wherein: X is fluoro, chloro, bromoor iodo; R¹ is selected from the group consisting of acyl, substitutedacyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl,substituted arylalkyl, cycloalkyl, substituted cycloalkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl andsubstituted heteroarylalkyl; R² and R³ are independently selected fromthe group consisting of hydrogen, alkyl, substituted alkyl,alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl,arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl and substitutedheteroarylalkyl or optionally, R² and R³ together with the carbon atomto which they are bonded form a cycloalkyl, substituted cycloalkyl,cycloheteroalkyl or substituted cycloheteroalkyl ring; R⁴ is selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, aryldialkylsilyl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl,substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl ortrialkylsilyl; and R⁵ is 4-cholorophenyl.
 54. The method of claim 53,wherein R⁴ is hydrogen.
 55. The method of claim 53 wherein R¹ isselected from C₁₋₆ alkyl, substituted C₁₋₆ alkyl, C₃₋₆ cycloalkyl,phenyl, substituted phenyl, C₇₋₉ phenylalkyl and pyridyl.
 56. The methodof claim 53, wherein R¹ is selected from methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl,phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 2-pyridyl, 3-pyridyl and 4-pyridyl.57. The method of claim 53, wherein R¹ is selected from methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, sec-pentyl, neopentyl, 1,1-diethoxyethyl, phenyl, cyclohexyland 3-pyridyl.
 58. The method of claim 53, wherein R² and R³ areindependently selected from hydrogen, C₁₋₄ alkyl, substituted C₁₋₄alkyl, C₁₋₄ alkoxycarbonyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkoxycarbonyl,phenyl, substituted phenyl, C₇₋₉ phenylalkyl and pyridyl.
 59. The methodof claim 53, wherein R² is selected from hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl,isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl,2-pyridyl, 3-pyridyl and 4-pyridyl, and R³ is hydrogen.
 60. The methodof claim 53 wherein R² is selected from hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, phenyl, or cyclohexyland R³ is hydrogen.
 61. The method of claim 53, wherein R² is selectedfrom methyl, methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl andcyclohexyloxycarbonyl and R³ is methyl.
 62. The method of claim 53,wherein R⁴ is selected from hydrogen, C₁₋₆ alkyl, substituted C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, substituted phenyl, C₇₋₉ phenylalkyl,substituted C₇₋₉ phenylalkyl, trialkylsilyl and aryldialkylsilyl. 63.The method of claim 53, wherein R⁴ is selected from hydrogen, methyl,ethyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl, diphenylmethyl,triphenylmethyl, trimethylsilyl, triethylsilyl, triisopropylsilyl,tert-butyldimethylsilyl and phenyldimethylsilyl.
 64. The method of claim53, wherein R⁴ is selected from hydrogen, allyl, benzyl andtrimethylsilyl.
 65. The method of claim 53, wherein: R¹ is selected frommethyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, phenyl, cyclohexyl, and 3-pyridyl; R² is selected fromhydrogen, methyl, n-propyl, and isopropyl; R³ is hydrogen; and R⁴ ishydrogen.
 66. The method of claim 53, wherein R² is methyl.
 67. Themethod of claim 53, wherein R² is isopropyl.
 68. The method of claim 67,wherein R¹ is isopropyl.
 69. The method of claim 53, wherein the organicbase is selected from triethylamine, tributylamine,diisopropylethylamine, dimethylisopropylamine, N-methylmorpholine,N-methylpyrrolidine, N-methylpiperidine, pyridine, 2-methylpyridine,2,6-dimethylpyridine, 4-dimethylaminopyridine, 1,4-diazabicyclo[2.2.2]octane, 1, 8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]undec-7-ene and a combination thereof.